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

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

Epidemiological parameters of malaria infection for site preparation of antimalarial monoclonal antibody studies in Torodo, Mali (ASTMH 2022) - "In prelude of antimalarial monoclonal The CIS43LS/L9LS study site preparation, the Immunogenetics Laboratory of the Malaria Research and Training Center in collaboration with the National institute of health (NIH) has undertaken a study that aims to assess the prevalence of malaria. The prevalence of P. falciparum malaria in Torodo in 2020 was high in general and children aged 11-17 were the most affected. . The coverage and ITNs was high. This setting could be ready to serve as potential site for the recruitment of volunteers to participate to the CIS43LS study."

Clinical • Late-breaking abstract • Anemia • Hematological Disorders • Infectious Disease • Malaria

The potential public health impact of novel malaria monoclonal antibody interventions (ASTMH 2022) - "Modelled mAbs characteristics are informed by pharmacokinetics (PK) and pharmacodynamics (PD) data from the first human mAb candidates CIS43LS and L9LS. Candidates with rapidly decaying protection are likely to achieve less impact and a single deployment in perennial settings may not be sufficient to reduce incidence by 50%. While early mAb candidates have demonstrated safety and protection against infection in early clinical trials, our modelling highlights the need to understand better their PK/PD properties and implementation factors for different use-cases and standard of care comparators to best inform candidate selection."

Infectious Disease • Malaria

A Phase 1, Open-Label, Dose Escalation and Route Optimization Trial with Controlled Human Malaria Infection to Evaluate Protective Efficacy of an Anti-Malaria Human Monoclonal Antibody in Healthy Malaria-naïve Adults (ASTMH 2022) - "Volunteers were treated with atovaquone-proguanil or terminally treated at Day 21. We conclude that volunteers dosed at 5 mg/kg or greater by iv or sc were protected following CIS43LS inoculation at 8 weeks. These findings show that mAbs can mediate protection at low doses and by the sc route providing data that this approach may be useful across a number of clinical use cases."

Clinical • P1 data • Infectious Disease • Malaria

Safety and Efficacy of a Monoclonal Antibody against Malaria in Mali. (PubMed, N Engl J Med) - P2 | "CIS43LS was protective against P. falciparum infection over a 6-month malaria season in Mali without evident safety concerns. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04329104.)."

Journal • Allergy • Immunology • Infectious Disease • Malaria • Pain

Anti-malaria MAb in Mali (clinicaltrials.gov) - P2 | N=348 | Active, not recruiting | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Completed ➔ Active, not recruiting | Trial completion date: Jan 2022 ➔ Jul 2023

Enrollment closed • Trial completion date • Infectious Disease • Malaria

Anti-malaria MAb in Mali (clinicaltrials.gov) - P2 | N=348 | Completed | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Recruiting ➔ Completed

Trial completion • Infectious Disease • Malaria

VRC 612: Trial to Evaluate CIS43LS in Healthy Adults (clinicaltrials.gov) - P1 | N=71 | Completed | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Active, not recruiting ➔ Completed | N=40 ➔ 71 | Trial completion date: Feb 2023 ➔ Apr 2022

Enrollment change • Trial completion • Trial completion date • Infectious Disease • Malaria

VRC 612: Trial to Evaluate CIS43LS in Healthy Adults (clinicaltrials.gov) - P1 | N=40 | Active, not recruiting | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Trial completion date: Feb 2022 ➔ Feb 2023

Trial completion date • Infectious Disease • Malaria