PfSPZ Vaccine / Sanaria - LARVOL DELTA

Safety Evaluation of PfSPZ Vaccine in Pregnant Women in Mali (MalVIP1) (clinicaltrials.gov) - P1 | N=0 | Withdrawn | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | N=400 ➔ 0 | Suspended ➔ Withdrawn

Enrollment change • Trial withdrawal • Infectious Disease • Malaria

Pan-African hybridization of PfSPZ increases antigenic diversity and replicative capacity for malaria vaccine design. (PubMed, JCI Insight) - "The hybrid, AV27, was selected for development based on balanced contribution of parental genomes, high PfSPZ production and high liver stage infectivity. As compared to NF54-based PfSPZ vaccines, we expect AV27-based vaccines will have greater and broader efficacy at lower doses due to higher liver stage infectivity and inclusion of unique East African CD8+ T cell epitopes."

Journal • Infectious Disease • Malaria • CD8

Optimal control and cost-effectiveness analysis of PfSPZ vaccination and indoor residual spraying in malaria transmission: a case study in Keerom. (PubMed, Front Public Health) - "The model considers the potential impact of the new PfSPZ vaccine and IRS through a novel host-vector framework...In particular, the combined strategy produces the largest reduction in the number of infected individuals, while the IRS-only strategy gives the most favorable cost-effectiveness outcome. These results suggest that PfSPZ vaccination and IRS can provide important benefits for malaria control in high-endemic areas such as Keerom, Papua."

HEOR • Journal • Infectious Disease • Malaria

Safety Evaluation of PfSPZ Vaccine in Pregnant Women in Mali (MalVIP1) (clinicaltrials.gov) - P1 | N=400 | Suspended | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Trial completion date: Nov 2025 ➔ Nov 2026 | Trial primary completion date: Nov 2025 ➔ Nov 2026

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

Successful insertion and expression of a tetracycline transactivator in Anopheles stephensi associated with increased egg production and decreased hatching rate. (PubMed, Parasit Vectors) - "Since PfSPZ vaccines are intended primarily for some of the most disadvantaged people in the world, keeping costs low is imperative. stephensi. The next step will be to cross the driver line with an effector line containing a male-linked lethal gene regulated by the tetracycline responsive element (TRE)."

Journal • Infectious Disease • Malaria

The Role of Long lasting IgM in Protection from the Liver Stage of Plasmodium falciparum (ASTMH 2025) - "To understand the role humoral immunity could play in long-lasting immunity, we applied a systems antibody approach where we profiled the Fc- and Fab- humoral profiles that were associated with protection from Pf malaria for more than a year in the VRC314 clinical trial of the radiation attenuated Sanaria® PfSPZ Vaccine...The PfSPZ invasion inhibition capacity of the purified IgM was associated with durability of vaccine-induced protection. Further, B cell receptor sequencing of cells from a subgroup of vaccinees identified that PfCSP-specific IgM and non-IgM plasmablasts have similar amounts of somatic hypermutation, all together suggesting that poly-antigenic IgM antibodies provide a long-lasting protective immune response against the pre-erythrocytic stages of malaria."

Late-breaking abstract • Infectious Disease • Malaria

Putative protective targets of whole-sporozoite vaccination identified in three field trials of PfSPZ vaccine through whole genome sieve analysis (ASTMH 2025) - "Comparison of these target loci with those previously found in Burkina Faso and Mali revealed five shared protein-coding genes, including PF3D7_ 1335900, which encodes thrombospondin-related anonymous protein (TRAP). The identification of PF3D7_1335900 as a potential protection target of PfSPZ vaccination in all three SAWG studies strongly supports the inclusion this gene in future vaccine formulations."

Late-breaking abstract • Infectious Disease • Malaria

A safe start for PfSPZ Vaccine, but efficacy in children remains elusive. (PubMed, Lancet Infect Dis) - No abstract available

Journal

Safety, tolerability, and protective efficacy of a radiation-attenuated, whole sporozoite malaria vaccine in children in Gabon: a randomised, double-blind, placebo-controlled, phase 2 trial. (PubMed, Lancet Infect Dis) - P2 | "PfSPZ Vaccine is well tolerated and safe, but it did not prevent P falciparum infection in children in Gabon. Whether presumptive treatment during immunisation or more potent PfSPZ vaccines can establish vaccine efficacy is currently under investigation."

Journal • P2 data • Allergy • Immunology • Infectious Disease • Malaria

Vaccines for pregnancy malaria—progress and possibilities (ASRI 2025) - "Recent advances in structural understanding of VAR2CSA will benefit vaccine design to direct antibody responses to conserved epitopes. Another vaccine approach being tested involves administration of an anti-infection vaccine during or prior to pregnancy; PfSPZ Vaccine is a promising candidate that has demonstrated excellent safety and protective efficacy in women of childbearing potential, and is poised to start trials in pregnant women."

Infectious Disease • Inflammation • Malaria

Successful insertion and expression of a tetracycline transactivator in Anopheles stephensi associated with increased egg production and decreased hatching rate. (PubMed, Res Sq) - "Since PfSPZ vaccines are intended primarily for some of the most disadvantaged people in the world, keeping costs low is imperative. The homozygous line produced ~ 18% more eggs per female and a hatching rate of larvae from eggs was 39% lower than of wild-type A. stephensi . The next step will be to cross the driver line with an effector line containing a male-linked lethal gene regulated by the tetracycline responsive element (TRE)."

Journal • Infectious Disease • Malaria

Safety, tolerability and immunogenicity of a condensed, multi-dose prime regimen of PfSPZ Vaccine for the prevention of Plasmodium falciparum malaria infection. (PubMed, Malar J) - P1 | "The two-dose priming immunization regimen was safe, well tolerated and highly immunogenic. Larger studies may better define the adverse event profile of condensed regimens of PfSPZ Vaccine in malaria-naive adults."

Clinical • Journal • Fatigue • Infectious Disease • Malaria • Musculoskeletal Pain • Pain

Protective targets of PfSPZ vaccines identified from whole-genome sieve analysis of isolates from malaria vaccine efficacy trials in West Africa. (PubMed, medRxiv) - "Among these was the thrombospondin-related anonymous protein locus, which encodes PfSSP2|TRAP, one of the most abundant and well-characterized pre-erythrocytic stage antigen as well as other genes encoding membrane-associated proteins of unknown function. These results identify SA WG as a potentially powerful tool for identifying protective vaccine antigens in recombining pathogens with large genome size and reveals potential new protective Pf antigens."

Clinical • Journal • Infectious Disease • Malaria

Safety Evaluation of PfSPZ Vaccine in Pregnant Women in Mali (MalVIP1) (clinicaltrials.gov) - P1 | N=400 | Suspended | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Trial completion date: Nov 2024 ➔ Nov 2025 | Trial primary completion date: Nov 2024 ➔ Nov 2025

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

A Phase 1 Trial of PfSPZ Vaccine in Healthy Adults to Determine Safety, Tolerability and Efficacy Against Heterologous CHMI (clinicaltrials.gov) - P1 | N=31 | Terminated | Sponsor: Sanaria Inc. | N=60 ➔ 31

Enrollment change • Infectious Disease • Malaria

Effects of baseline characteristics, peri-conception factors, and post-vaccination responses on fertility outcomes on Malian women of childbearing potential at risk for Plasmodium falciparum (Pf) malaria who received attenuated whole-sporozoite . (ASTMH 2024) - "We are conducting an exploratory post hoc analysis of the impact on time to conception of the following baseline characteristics and peri-conception factors collected during the PfSPZ Vaccine trial: age at conception, method and duration of contraception, presence of parasitemia at baseline by blood smear and qPCR, time of contraception discontinuation, time of last dose of vaccine or placebo, time of last episode of parasitemia, gravidity status of participants, increases in anti-PfCSP antibody levels and malaria season. The results of these ongoing analyses will be presented."

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

Dynamics of antibody specific to the placental malaria vaccine candidate VAR2CSA during pregnancies of women who received pre-conception PfSPZ Vaccine (ASTMH 2024) - "Assays to evaluate the inhibition activity of the sera are ongoing to explore whether this critical function of antibody in PM is reduced by pre-conception PfSPZ Vaccine. Effect of antigenic variation in the antibody activity will also be explored."

Clinical • Late-breaking abstract • Infectious Disease • Malaria

Pre-existing antibody reduces Radiation Attenuated Sporozoites (RAS) vaccine response, by blocking RAS invasion of liver in C57BL/6 mice. (ASTMH 2024) - "The whole sporozoite PfSPZ Vaccine confers high protective efficacy in malaria-naïve adults, with 100% and 83% vaccine efficacy (VE), respectively, against homologous and heterologous controlled human malaria infection (CHMI)...Nevertheless, three doses of 1x10 4 Pb RAS induced similar robust CD8 T cell responses (total and antigen-specific) in the two groups, and VE was 100% in both groups following challenge with IV sporozoites. We are now evaluating the durability of protection in the mice, as well as assessing the impact of pre-existing antibodies on immunogenicity and efficacy of lower PbSPZ vaccine doses."

Late-breaking abstract • Preclinical • Infectious Disease • Malaria • CD8

Protection of Indonesian soldiers against highly variant Plasmodium falciparum infection in Papua Province, Indonesia, by two PfSPZ vaccines (ASTMH 2024) - "Molecular subunit vaccines RTS,S/AS01 and R21/Matrix-M have achieved 45-77% VE against febrile high-grade Pf parasitemia in African infants and small children but only nominal protection against Pf infection, a more stringent endpoint...There was no VE against P. vivax . PfSPZ Vaccine and PfSPZ-CVac (CQ) had 50-56% VE over 24 weeks in non-immune soldiers against Pf infection and clinical malaria caused by a Pf population that is, globally, the most divergent from the vaccine strain."

Infectious Disease • Malaria

Differences in innate cellular immune responses distinguish protected from not protected individuals in a PfSPZ Vaccine trial (ASTMH 2024) - "Consistent with previous studies, Vδ2 γδ T cells were increased in protected vaccinees. A unique finding was that MAIT cells, which span the innate and adaptive arms of the immune response, were significantly elevated in protected compared to non-protected vaccinees - a finding requiring further studies."

Clinical • Infectious Disease • Malaria • CD4 • CD8 • DPP4 • IFNG • IL2 • KLRB1

PfSPZ Vaccine elicits PfCSP antibodies that cross-react with other P. falciparum proteins and correlate with protection from malaria (ASTMH 2024) - "Hierarchical clustering grouped cross-reactive responses into high and low groups with a higher proportion of protected vaccinees clustering into the high group. This work highlights the importance of considering the possibility of broadly cross-reactive antibodies in seroprofiling studies and demonstrates a correlation between broad seroreactivity and vaccine efficacy."

Infectious Disease • Malaria

Creating superior PfSPZ vaccines for malaria by genetically crossing West and East African Plasmodium falciparum to produce PfSPZ with greater antigenic diversity and potency (ASTMH 2024) - "This resulted in identification of 2 pan African recombinant hybrids, AV27 & AVD7, that met all criteria. We are creating late arresting replication competent parasites, PfSPZ-LARC2 (AV27 & AVD7), by deleting genes for Mei2 and LINUP , and plan GMP production and clinical trials."

Infectious Disease • Malaria • CD8

PfSPZ Vaccine induces focused humoral immune response in HIV positive and negative Tanzanian adults. (PubMed, EBioMedicine) - "Our data demonstrate that HIV infection does not affect the quantity of the total IgG and IgM antibody responses to PfCSP and PfMSP5 after immunization with PfSPZ Vaccine. PfMSP5 represents a highly immunogenic, so far underexplored, target for vaccine-induced antibodies in malaria pre-exposed volunteers."

Journal • Human Immunodeficiency Virus • Infectious Disease • Malaria

Safety and efficacy of PfSPZ Vaccine against malaria in healthy adults and women anticipating pregnancy in Mali: two randomised, double-blind, placebo-controlled, phase 1 and 2 trials. (PubMed, Lancet Infect Dis) - P1, P2 | "PfSPZ Vaccine was safe and well tolerated in adults in Mali. The 9 × 105 and 1·8 × 106 doses of PfSPZ Vaccine administered as per the 4-week schedule, which incorporated presumptive antimalarial treatment before the first vaccine dose, showed significant efficacy against P falciparum parasitaemia and clinical malaria for two malaria transmission seasons in women of childbearing age and against pregnancy malaria. PfSPZ Vaccine without presumptive antimalarial treatment before the first vaccine dose did not show efficacy."

Journal • P1 data • Allergy • Gastroenterology • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammation • Malaria • Obstetrics

Immune responses associated with protection induced by chemoattenuated PfSPZ vaccine in malaria-naive Europeans. (PubMed, JCI Insight) - "Vaccination of malaria-naive volunteers with a high dose of Plasmodium falciparum sporozoites chemoattenuated by chloroquine (CQ) (PfSPZ-CVac [CQ]) has previously demonstrated full protection against controlled human malaria infection (CHMI)...In a cohort from a malaria-endemic area in Gabon, these CD8+ T cell clusters were also associated with parasitemia control in individuals with lifelong exposure to malaria. Upon stimulation with P. falciparum-infected erythrocytes, CD4+, γδ, and EMRA CD8+ T cells produced IFN-γ and/or TNF, indicating their ability to mediate responses that eliminate malaria parasites."

Clinical • Journal • Infectious Disease • Malaria • CD4 • CD8 • IFNG • NCAM1