A Monoclonal Antibody for Malaria Prevention

Gaudinski, Martin R.; Berkowitz, Nina M.; Idris, Azza H.; Coates, Emily E.; Holman, LaSonji A.; Mendoza, Floreliz; Gordon, Ingelise J.; Plummer, Sarah H.; Trofymenko, Olga; Hu, Zonghui; Chagas, Andrezza Campos; O’Connell, Sarah; Basappa, Manjula; Douek, Naomi; Narpala, Sandeep; Barry, Christopher R.; Widge, Alicia T.; Hicks, Renunda; Awan, Seemal F; Wu, Rongxue; Hickman, Somia P.; Wycuff, Diane; Stein, Judy; Case, Christopher L.; Evans, Brian P.; Carlton, Kevin; Gall, Jason; Vazquez, Sandra; Flach, Britta; Chen, Grace L.; Francica, Joseph R.; Flynn, Barbara J.; Kisalu, Neville K.; Capparelli, Edmund V.; McDermott, Adrian B.; Mascola, John R.; Ledgerwood, Julie E.; Seder, Robert A.

doi:10.1056/nejmoa2034031

Cited by 111 publications

(96 citation statements)

References 35 publications

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“…In terms of the clinical implications of these findings, CIS43 has completed Phase 1 testing [ 24 ]. The results of this study indicated that this anti-JR mAb can safely and effectively prevent Pf malaria following controlled exposure to infected mosquitoes and confirm that the JR is required for protection in humans.…”

Section: Discussionmentioning

confidence: 99%

The P. falciparum CSP repeat region contains three distinct epitopes required for protection by antibodies in vivo

et al. 2021

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Rare and potent monoclonal antibodies (mAbs) against the Plasmodium falciparum (Pf) circumsporozoite protein (CSP) on infective sporozoites (SPZ) preferentially bind the PfCSP junctional tetrapeptide NPDP or NVDP minor repeats while cross-reacting with NANP central repeats in vitro. The extent to which each of these epitopes is required for protection in vivo is unknown. Here, we assessed whether junction-, minor repeat- and central repeat-preferring human mAbs (CIS43, L9 and 317 respectively) bound and protected against in vivo challenge with transgenic P. berghei (Pb) SPZ expressing either PfCSP with the junction and minor repeats knocked out (KO), or PbCSP with the junction and minor repeats knocked in (KI). In vivo protection studies showed that the junction and minor repeats are necessary and sufficient for CIS43 and L9 to neutralize KO and KI SPZ, respectively. In contrast, 317 required major repeats for in vivo protection. These data establish that human mAbs can prevent malaria infection by targeting three different protective epitopes (NPDP, NVDP, NANP) in the PfCSP repeat region. This report will inform vaccine development and the use of mAbs to passively prevent malaria.

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Section: Discussionmentioning

confidence: 99%

The P. falciparum CSP repeat region contains three distinct epitopes required for protection by antibodies in vivo

et al. 2021

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“…This is an important issue for the clinical development of PfCSP mAbs for malaria prophylaxis, as targeting two distinct PfCSP epitopes could lead to improved protection against malaria as has been seen with viral infections like HIV-1, Ebola, and SARS-CoV-2 [37,54,55]. A recent Phase 1 clinical trial showed that administration of CIS43 was safe and protected all nine CIS43-treated volunteers following controlled human malaria infection [56]. A similar clinical trial for L9 has recently been initiated; thus, it is possible that CIS43, L9, and other protective PfCSP mAbs might be combined in the future.…”

Section: Plos Pathogensmentioning

confidence: 99%

Protective effects of combining monoclonal antibodies and vaccines against the Plasmodium falciparum circumsporozoite protein

et al. 2021

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Combinations of monoclonal antibodies (mAbs) against different epitopes on the same antigen synergistically neutralize many viruses. However, there are limited studies assessing whether combining human mAbs against distinct regions of the Plasmodium falciparum (Pf) circumsporozoite protein (CSP) enhances in vivo protection against malaria compared to each mAb alone or whether passive transfer of PfCSP mAbs would improve protection following vaccination against PfCSP. Here, we isolated a panel of human mAbs against the subdominant C-terminal domain of PfCSP (C-CSP) from a volunteer immunized with radiation-attenuated Pf sporozoites. These C-CSP-specific mAbs had limited binding to sporozoites in vitro that was increased by combination with neutralizing human “repeat” mAbs against the NPDP/NVDP/NANP tetrapeptides in the central repeat region of PfCSP. Nevertheless, passive transfer of repeat- and C-CSP-specific mAb combinations did not provide enhanced protection against in vivo sporozoite challenge compared to repeat mAbs alone. Furthermore, combining potent repeat-specific mAbs (CIS43, L9, and 317) that respectively target the three tetrapeptides (NPDP/NVDP/NANP) did not provide additional protection against in vivo sporozoite challenge. However, administration of either CIS43, L9, or 317 (but not C-CSP-specific mAbs) to mice that had been immunized with R21, a PfCSP-based virus-like particle vaccine that induces polyclonal antibodies against the repeat region and C-CSP, provided enhanced protection against sporozoite challenge when compared to vaccine or mAbs alone. Collectively, this study shows that while combining mAbs against the repeat and C-terminal regions of PfCSP provide no additional protection in vivo, repeat mAbs do provide increased protection when combined with vaccine-induced polyclonal antibodies. These data should inform the implementation of PfCSP human mAbs alone or following vaccination to prevent malaria infection.

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“…Importantly, the 88% sterile protection was achieved using a low total dose of mAb (100 µg/mouse or ∼5 mg/kg). This total dose of 100 µg/mouse (50 µg/mouse each of anti-PfCSP and anti-PfTRAP mAb) is expected to give a total circulating mAb concentration of ∼20 µg/mL 45 —a level that can be achieved for ∼36 weeks with a single 20 mg/kg injection of long-lasting mAbs 52, 60, 61 or ∼4 years via active vaccination 62 . Although it remains to be seen how accurately these animal models translate to the clinic, these data suggest that reaching the 80% sterile protection threshold needed for vaccines 11 or injectable anti-malarials 15 that can be used as eradication tools may be achieved by targeting multiple proteins rather than by increasing the concentration of antibodies recognizing CSP alone.…”

Section: Discussionmentioning

confidence: 99%

“…Experience with RTS,S—which elicits extremely high peak levels of anti-CSP antibodies—as well as published data describing the activity of potent anti-CSP mAbs in animal models suggest that increasing anti-CSP antibody titers can increase protection 45, 55, 59 . The first CHMI trial using passive transfer of the anti-PfCSP mAb CIS43 (also used in this study) showed that mAbs can provide sterilizing protection against P. falciparum mosquito-bite infection at serum concentrations between ∼50–500 µg/mL 60 . However, maintenance of such high antibody titers for over a year may not be sustainable for active or passive immunization strategies.…”

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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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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A Monoclonal Antibody for Malaria Prevention

Cited by 111 publications

References 35 publications

The P. falciparum CSP repeat region contains three distinct epitopes required for protection by antibodies in vivo

The P. falciparum CSP repeat region contains three distinct epitopes required for protection by antibodies in vivo

Protective effects of combining monoclonal antibodies and vaccines against the Plasmodium falciparum circumsporozoite protein

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

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