VRC-MALMAB0100-00-AB / National Institute of Allergy and Infectious Diseases - LARVOL DELTA

Longitudinal malaria genotyping increases efficacy resolution for the malaria monoclonal antibody CIS43LS (ASTMH 2025) - "Enrollment infection also significantly modified efficacy for 40 mg/kg mAb: EffmolFOI was 90.2% [84.4 - 93.8] for enrollment-negative and 67.6% [39.9 - 82.6] for enrollment-positive subjects. We contrast our findings with time to first infection and other genotype-agnostic efficacy estimators, and we discuss how effects of seasonality, intrinsic risk heterogeneity, and pharmacokinetic variables can be resolved and accounted for using different endpoints."

Clinical • Infectious Disease • Malaria

Exploring the potential role of the neonatal Fc receptor genotype and IgG1 allotype on half-life variability of the anti-malaria monoclonal antibody CIS43LS (ASTMH 2025) - "IgG1 allotyping may offer valuable insights into how immunoglobulin genetic diversity affects mAb pharmacokinetics. A comprehensive evaluation of endogenous IgG levels, FCGRT genotypes, and IgG1 allotypes may help elucidate the determinants of inter-individual variability in CIS43LS pharmacokinetics and guide the development of optimized mAb strategies for malaria prevention in African settings."

Late-breaking abstract • Infectious Disease • Malaria • FCGRT

De novo design and experimental characterization of germline targeting vaccines against Plasmodium falciparum circumsporozoite protein (CSP) repeats (ASTMH 2025) - "Currently licensed pre-erythrocytic vaccines, RTS,S/AS01 and R21/Matrix-M, target the P. falciparum circumsporozoite protein (CSP) but exhibit limited durability and quality of antibody responses, potentially due to the exclusion of protective junctional (NPDP) and minor (NVDP) repeat epitopes. Clinical trials with NPDP-targeting CIS43LS and NVDP-targeting L9LS mAbs have demonstrated significant efficacy, validating these epitopes as vaccine targets...Moreover, L9 immunogens successfully recruited germline-L9 B cells to germinal centers, and cryo-EM structures confirmed precise scaffolding of L9 Fab-Fab complexes. These findings underscore the potential of deep learning-enabled protein design to develop next-generation malaria vaccines that elicit potent, conformation-specific protective antibody responses."

Late-breaking abstract • Infectious Disease • Malaria

Fine specificity in humoral immunity againstPlasmodium falciparumcircumsporozoite protein in humans immunized with radiation-attenuated sporozoites (ASTMH 2025) - "The two most advanced human mAbs, CIS43LS and L9LS, which preferentially target the junctional and minor repeat region of PfCSP respectively, can prevent malaria for over 6 months against intense seasonal transmission in children and adults. Based on the screening results, we selected several volunteers for anti-PfCSP-specific B cell isolation for the next high-throughput RATP-Ig screening. The serum reactivity results and the progress of mAb generation will be presented."

Late-breaking abstract • Infectious Disease • Malaria

Assessing the impact of endogenous IgG and IgG1 levels on the pharmacokinetics of the anti-malaria monoclonal antibodies CIS43LS and L9LS (ASTMH 2025) - "Similar analyses are ongoing for clinical trials of the long-acting anti-sporozoite mAb L9LS that were conducted in U.S. adults; Malian adults, children and infants; and Kenyan children. These data are contributing to an ongoing comprehensive analysis of the determinants of inter-population and inter-individual variability in the pharmacokinetics of CIS43LS and L9LS—information that can help inform the development and eventual implementation of therapeutic mAbs against malaria and other diseases in Africa."

Late-breaking abstract • PK/PD data • Infectious Disease • Malaria

Impact of monoclonal antibodies targeting Plasmodium falciparum circumsporozoite protein on vaccine-mediated immune responses (ASTMH 2025) - "Human clinical trials of the two most advanced, extended half-life mAbs in development, L9LS and CIS43LS, have demonstrated safety, tolerability, and sustained, high-level protection against P. falciparum infection in adults and children in intense, seasonal transmission settings...As such, administration of these mAbs prior to RTS,S or R21 raises concerns about potential immunological interference. To address this, we evaluated the immunogenicity and protective efficacy of the R21 vaccine following administration of anti-CSP mAbs in a pre-clinical malaria challenge model."

Late-breaking abstract • Infectious Disease • Malaria

Longitudinal malaria genotyping increases efficacy resolution for the malaria monoclonal antibody CIS43LS (ASTMH 2025) - "Enrollment infection also significantly modified efficacy for 40 mg/kg mAb: EffmolFOI was 90.2% [84.4 - 93.8] for enrollment-negative and 67.6% [39.9 - 82.6] for enrollment-positive subjects. We contrast our findings with time to first infection and other genotype-agnostic efficacy estimators, and we discuss how effects of seasonality, intrinsic risk heterogeneity, and pharmacokinetic variables can be resolved and accounted for using different endpoints."

Clinical • Infectious Disease • Malaria

Pharmacokinetic and pharmacodynamic analysis of the CIS43LS monoclonal antibody against malaria in a Phase 2 trial of Malian adults (ASTMH 2025) - P2 | "After CIS43LS administration, low-level anti-drug antibodies were transiently detected in 1 of 238 (0.4%) participants. These results indicate that protective levels of CIS43LS can be predictably maintained during a 6-month malaria season and support the continued development of antimalarial mAbs for use in populations at risk of malaria."

Clinical • P2 data • PK/PD data • Infectious Disease • Malaria

Anti-sporozoite monoclonal antibody for malaria prevention: secondary efficacy outcome of a phase 2 randomized trial. (PubMed, Nat Med) - P2 | "CIS43LS is a long-acting monoclonal antibody specific for the Plasmodium falciparum circumsporozoite protein expressed on sporozoites...At enrollment, all participants received artemether-lumefantrine to clear possible P. falciparum infection...These data indicate that a single dose of anti-sporozoite monoclonal antibodies can achieve durable, sterile protection against P. falciparum infection, underscoring their potential to reduce malaria disease burden and transmission. ClinicalTrials.gov identifier: NCT04329104 ."

Journal • P2 data • Infectious Disease • Malaria

Evaluation of antimalarial antibodies elicited by CSP-based vaccines in humanized immunoglobulin mice (IMMUNOLOGY 2025) - "Our results identified novel mAbs that provide protection comparable to CIS43LS, a leading clinical candidate that has demonstrated high efficacy in an endemic setting. These findings suggest that incorporating multiple epitopes in a vaccine can elicit Abs that bind subdominant epitopes and neutralize the parasite. Our insights can be leveraged to inform the design and development of prophylactic malaria antibodies and vaccines.Keywords: Animals Rodent; Cells B Cells; Infections Parasitic-Helminth; Molecules Antibodies; Techniques/Approaches Transgenic/Knockout Mice"

Preclinical • Infectious Disease • Malaria

FcγR binding differentially contributes to protection by two human monoclonal antibodies targeting Plasmodium falciparum circumsporozoite protein. (PubMed, Sci Transl Med) - "However, similar Fc modifications incorporated into L9LS did not increase protection compared to the parental mAb. Overall, although FcγR binding by CIS43LS and L9LS is dispensable in mouse models of malaria, enhancing the binding of CIS43LS to FcγR showed a modest increase in the potency of this mAb."

Journal • Infectious Disease • Malaria

Genotypic infection endpoint analysis to understand efficacy and escape potential of the malaria monoclonal antibody CIS43LS (ASTMH 2024) - "The observed polymorphisms are not correlated to study arm and thus unlikely associated with antibody escape. Our work demonstrates the value of complementing current trial designs with genotypic endpoints and also highlights various methodological innovations we have applied to boost assay sensitivity and integrate false-positive detection in a high-throughput context."

Clinical • Infectious Disease • Malaria

Interaction between naturally-acquired humoral immunity to malaria and the anti-malarial monoclonal antibody CIS43LS (ASTMH 2024) - "The same samples are being analyzed by a Pf protein microarray to extend this analysis. These data suggest that CIS43LS-mediated protection is associated with a lack of boosting in P. falciparum blood-stage-specific humoral immunity and increase in PfCSP-specific humoral immunity."

Late-breaking abstract • Infectious Disease • Malaria

A case of exposure to the antimalarial monoclonal antibody CIS43LS in pregnancy during a phase 2 trial in Kalifabougou, Mali. (ASTMH 2024) - "CIS43LS concentrations are being measured in cord blood at delivery; and at various timepoints in the participant’s serum and breastmilk, and in the infant’s serum through 12 months of age. This case report and the CIS43LS pharmacokinetic analysis of the pregnant participant and her infant will inform future trials of anti-sporozoite mAbs in pregnancy."

Clinical • Late-breaking abstract • P2 data • Infectious Disease • Malaria

Investigating the interaction between the anti-malaria monoclonal antibody CIS43LS and naturally acquired sporozoite-specific T cell responses in Malian adults (ASTMH 2024) - "Regulatory T cell responses were investigated by measuring the level of P. falciparum -inducible IL-10 in CD4+CD25+FoxP3- T cells, which play a critical role in regulating inflammation after P. falciparum infection. Our study may provide insights into the interaction between Pf CSP-specific monoclonal antibodies and naturally acquired P. falciparum -specific T cell responses."

Clinical • IO biomarker • Late-breaking abstract • Infectious Disease • Inflammation • Malaria • CD4 • CD40LG • CD8 • FOXP3 • IFNG • IL10 • IL2 • IL2RA • LAG3 • PD-1 • TNFA • TNFRSF9

Genotypic infection endpoint analysis to understand efficacy and escape potential of the malaria monoclonal antibody CIS43LS (ASTMH 2024) - "The observed polymorphisms are not correlated to study arm and thus unlikely associated with antibody escape. Our work demonstrates the value of complementing current trial designs with genotypic endpoints and also highlights various methodological innovations we have applied to boost assay sensitivity and integrate false-positive detection in a high-throughput context."

Clinical • Infectious Disease • Malaria

Anti-malaria MAb in Mali (clinicaltrials.gov) - P2 | N=348 | Completed | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Active, not recruiting ➔ Completed

Trial completion • Infectious Disease • Malaria

Prophylactic malaria monoclonal antibody MAM01 showed extensive binding breath to Circumsporozoite protein repeat region epitopes (ASTMH 2023) - "MAbs such as CIS43LS and L9LS are in development for malaria prevention in multiple clinical use cases...Overall, MAM01 demonstrated a broad range of cross-reactivity to CSP epitopes and a strong Fc effector function in vitro. Further determination of clinical significance of MAM01 can help expand prophylaxis options for malaria treatment."

Late-breaking abstract • Infectious Disease • Malaria

The impact of the anti-malarial monoclonal antibody CIS43LS on naturally acquired sporozoite-specific T cell responses in Malian adults (ASTMH 2023) - "PBMCs are stimulated with P. falciparum sporozoites and analyzed with a flow cytometry panel that includes nine immune cell markers (CD3, CD4, CD8, CD14, CD16, CD19, CD25, CD56, and Fox P3) and four cytokines (IFN-γ, IL-2, TNF-α, and IL-10). Our study may provide insight into the interaction between Pf CSP-specific monoclonal antibodies and naturally acquired sporozoite-specific T cell responses."

Clinical • Late-breaking abstract • Infectious Disease • Malaria • CD14 • CD8 • IFNG • IL10 • IL2 • IL2RA • NCAM1 • TNFA

MAM01 and L9LS Demonstrate Equipotent Protection Against Plasmodium falciparum (Pf) Malaria Infection in Mice (ASTMH 2023) - "The efficacy of MAM01 was compared to two comparator antibodies L9LS and CIS43LS. In the liver burden assay, which has a continuous readout, approximately 40 µg/m L of MAM01 provided 95% protection from infection; similar levels of protection in the parasitemia assay, which has a binary readout (infected or protected), required a higher concentration (approximately 140 µg/m L). The equipotency of MAM01 with L9LS, which recently conferred protection in a human challenge model supports further development of MAM01."

Late-breaking abstract • Preclinical • Infectious Disease • Malaria

Secondary Analyses of a Phase 2 Trial of the Anti-malaria Monoclonal Antibody CIS43LS in Mali (ASTMH 2023) - No abstract available

P2 data • Infectious Disease • Malaria

51 - Clinical Development of Monoclonal Antibodies that Target Malaria Sporozoites (ASTMH 2023) - "The aim of this symposium is to bring together leaders in the field to present results from pivotal phase 2 trials of CIS43LS and L9LS in Mali and Kenya, and to review progress in the development of the MAM01 mAb. The symposium will provide a forum for the community to discuss next steps in the clinical development and registration of mAbs including potential targeted populations. Each presenter will provide an overview on prior experience exploring some of these concepts in prior and current projects, but also will discuss important concepts to explore in future mAb clinical trials."

Clinical • Infectious Disease • Malaria

Assessing the interaction between naturally-acquired PfCSP-specific humoral immunity and the protective efficacy of the anti-malarial monoclonal antibody CIS43LS (ASTMH 2023) - "The relationship between pre-existing antibody levels and CIS43LS efficacy will be determined, and naturally acquired antibody responses to Pf CSP and blood-stage antigens in those who received CIS43LS, or placebo will be compared. This analysis may provide insight into whether CIS43LS efficacy varies with background levels of Pf CSP-specific humoral immunity (i.e. vary with age and malaria transmission intensity) and the extent to which naturally acquired humoral immunity to the pre-erythrocytic and erythrocytic stages of P. falciparum might be impacted by CIS43LS."

Clinical • Infectious Disease • Malaria

Low-dose intravenous and subcutaneous CIS43LS monoclonal antibody for protection against malaria (VRC 612 Part C): a phase 1, adaptive trial. (PubMed, Lancet Infect Dis) - P1 | "CIS43LS was safe and well tolerated, and conferred protection against P falciparum at low doses and by the subcutaneous route, providing evidence that this approach might be useful to prevent malaria across several clinical use cases."

Journal • P1 data • Allergy • Immunology • Infectious Disease • Malaria

Baseline characteristics of participants in a phase 2 trial in Mali of CIS43LS, a monoclonal antibody against malaria (ASTMH 2022) - "Here we describe the baseline characteristics of subjects enrolled in this trial.Results : In the efficacy phase of the trial, 330 participants were enrolled before the malaria season, dosed with artemether-lumefantrine, and randomly assigned and received a single intravenous infusion of study agent: 110 received 10 mg/kg of CIS43LS, 110 received 40 mg/kg of CIS43LS, and 110 received placebo. In this phase 2 trial of CIS43LS in Malian adults, baseline characteristics were similar across study arms and the prevalence of asymptomatic P. falciparum at enrollment before the malaria season was low by blood smear."

Late-breaking abstract • P2 data • Infectious Disease • Malaria