L9LS / National Institute of Allergy and Infectious Diseases - LARVOL DELTA

L9LS MAb in Malian Infants (clinicaltrials.gov) - P1 | N=327 | Completed | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Active, not recruiting ➔ Completed | N=180 ➔ 327

Enrollment change • Trial completion • Infectious Disease • Malaria

The promise of monoclonal antibody interventions in malaria: A narrative review. (PubMed, Clin Microbiol Infect) - "Current evidence indicates that long-acting monoclonal antibodies have the potential to complement existing malaria control strategies by providing rapid, highly effective, and durable protection, particularly for populations at greatest risk of infection, including young children, pregnant women and individuals in seasonal transmission settings. Continued optimization of antibody potency, durability, delivery platforms, together with the identification of robust immune correlates of protection, will be critical for integrating monoclonal antibodies into future malaria control programs."

Journal • Review • Infectious Disease • Malaria

Quantitative and Clinical Pharmacology Perspectives on Next-Generation Malaria Prevention Using Vaccines and Long-Acting Monoclonal Antibodies. (PubMed, Clin Transl Sci) - "Vaccines such as RTS,S/AS01 and R21/Matrix-M induce active immunity through polyclonal antibody and CD4+ T-cell responses against the circumsporozoite protein (CSP), providing durable, population-level protection. In contrast, mAbs including CIS43LS and L9LS confer immediate, passive immunity, with protection directly linked to systemic exposure and duration above protective thresholds...This review emphasizes how quantitative PK/PD and PBPK modeling provide a framework to optimize dosing, predict durability of protection, and guide clinical development across diverse populations. These strategies underscore the value of model-informed translational pharmacology in accelerating development of next-generation malaria preventive interventions against malaria."

Journal • Review • Infectious Disease • Malaria • Pediatrics • CD4

L9LS-pd: Monoclonal Antibodies in Children With Severe Anaemia or Severe Malaria to Prevent Malaria After Hospital Discharge (clinicaltrials.gov) - P3 | N=398 | Active, not recruiting | Sponsor: Liverpool School of Tropical Medicine | Recruiting ➔ Active, not recruiting

Enrollment closed • Head-to-Head • Anemia • Hematological Disorders • Infectious Disease • Malaria

L9LS in Women of Childbearing Potential in Mali (clinicaltrials.gov) - P2 | N=279 | Completed | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Recruiting ➔ Completed

Trial completion • Infectious Disease • Malaria

Safety and efficacy of the monoclonal antibody L9LS for malaria prevention in children exposed to perennial malaria transmission in Kenya: a randomised, double-blind, placebo-controlled, phase 2 trial. (PubMed, Lancet) - P2 | "L9LS was protective against malaria in young children in western Kenya without evident safety concerns over 6-12 months. A higher dose of L9LS might be needed to achieve high-level efficacy against malaria in young children exposed to intense perennial P falciparum transmission."

Clinical • Journal • P2 data • Infectious Disease • Malaria

L9LS-R21 Interaction (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | N=357 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Infectious Disease • Malaria

L9LS-R21 Interaction (clinicaltrials.gov) - P2 | N=357 | Not yet recruiting | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Trial completion date: Nov 2028 ➔ Mar 2029 | Initiation date: Nov 2025 ➔ Mar 2026 | Trial primary completion date: Nov 2027 ➔ Mar 2028

Trial completion date • Trial initiation date • Trial primary completion date • Infectious Disease • Malaria

Efficacy and safety of Monoclonal Antibodies in Malaria Protection and Prevention of Transmission: A Systematic Review. (PubMed, Clin Ther) - "Antimalarial mAbs show promise as scalable tools for malaria prevention and transmission reduction. Subcutaneous delivery and prolonged protection enhance their feasibility for integration into the public health system for wider implementation in community settings. Further large-scale trials assessing long-term efficacy, operational feasibility, and cost-effectiveness in diverse settings, including children and pregnant women, are required and will govern the feasibility of its use in wider community settings."

Journal • Review • Fatigue • Infectious Disease • Malaria • Pain

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

Design of a Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Effect of the Anti-sporozoite Monoclonal Antibody L9LS on R21/Matrix-MTM Vaccine Immunogenicity (ASTMH 2025) - "A high priority potential use case for L9LS is malaria prevention in infants before they complete the 3-dose series of RTS,S/AS01 (RTS,S) or R21/Matrix-M™ (R21) at 7-9 months of age...Primary study objectives include evaluation of the safety and tolerability of L9LS and R21 when administered in close succession, as well as R21 immunogenicity (total IgG anti-NANP titers) at 28 and 84 days following the 3rd and 4th dose of R21. Additional study evaluations include L9LS pharmacokinetics, anti-drug antibody assessments, and Pf infection and clinical malaria risk."

Clinical • P2 data • Infectious Disease • Malaria

Field-deployable targeted nanopore sequencing to assess Plasmodium falciparum circumsporozoite genetic variability in western Kenya (ASTMH 2025) - "The two currently approved malaria vaccines (RTS,S and R21), along with candidate monoclonal antibodies (L9LS), target the central repeat and C-terminal domains of Plasmodium falciparum (Pf) circumsporozoite protein (csp)...These findings underscore extensive csp diversity in western Kenya (a high transmission setting), including polymorphisms in vaccine antigen targets. Rapid and locally deployable nanopore genomic surveillance could help detect csp escape variants and facilitate improved monitoring of vaccine effectiveness at a population level in Africa."

Infectious Disease • Malaria • CD4 • CD8

Anti-malaria MAb in Kenyan Children (clinicaltrials.gov) - P2 | N=912 | Completed | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | N=420 ➔ 912

Enrollment change • Infectious Disease • Malaria

L9LS-R21 Interaction (clinicaltrials.gov) - P2 | N=357 | Not yet recruiting | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

New P2 trial • Infectious Disease • Malaria

L9LS MAb in Malian Infants (clinicaltrials.gov) - P1 | N=180 | Active, not recruiting | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Trial completion date: Aug 2025 ➔ Jun 2026 | Recruiting ➔ Active, not recruiting

Enrollment closed • Trial completion date • Infectious Disease • Malaria

L9LS in Women of Childbearing Potential in Mali (clinicaltrials.gov) - P2 | N=290 | Recruiting | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Not yet recruiting ➔ Recruiting

Enrollment open • Infectious Disease • Malaria

L9LS in Women of Childbearing Potential in Mali (clinicaltrials.gov) - P2 | N=290 | Not yet recruiting | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

New P2 trial • Infectious Disease • Malaria

L9LS-pd: Monoclonal Antibodies in Children With Severe Anaemia or Severe Malaria to Prevent Malaria After Hospital Discharge (clinicaltrials.gov) - P3 | N=398 | Recruiting | Sponsor: Liverpool School of Tropical Medicine

Head-to-Head • New P3 trial • Anemia • Hematological Disorders • 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

L9LS MAb in Malian Adults (clinicaltrials.gov) - P2 | N=490 | Completed | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | N=288 ➔ 490

Enrollment change • Infectious Disease • Malaria

190 - Clinical Development of Monoclonal Antibodies that Target Malaria Sporozoites (ASTMH 2024) - "The aim of this symposium is to bring together leaders in the field to present results from Phase 2 trials of L9LS in Mali and Kenya, and a Phase 1 Challenge Study in the US for MAM01. 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. Ample time will be provided at the end of the symposium to promote Q&A and discussion from the audience."

Clinical • Infectious Disease • Malaria

Safety, Pharmacokinetics, and Efficacy of Repeated Dosing of L9LS in Kenyan Infants and Children (ASTMH 2024) - No abstract available

Clinical • PK/PD data • Infectious Disease • Malaria