A Pfs48/45-based vaccine to block Plasmodium falciparum transmission: phase 1, open-label, clinical trial.

BACKGROUND: The stalling global progress in malaria control highlights the need for novel tools for malaria elimination, including transmission-blocking vaccines. Transmission-blocking vaccines aim to induce human antibodies that block parasite development in the mosquito and mosquitoes becoming infectious. The Pfs48/45 protein is a leading Plasmodium falciparum transmission-blocking vaccine candidate. The R0.6C fusion protein, consisting of Pfs48/45 domain 3 (6C) and the N-terminal region of P. falciparum glutamate-rich protein (R0), has previously been produced in Lactococcus lactis and elicited functional antibodies in rodents. Here, we assess the safety and transmission-reducing efficacy of R0.6C adsorbed to aluminium hydroxide with and without Matrix-M™ adjuvant in humans. METHODS: In this first-in-human, open-label clinical trial, malaria-naïve adults, aged 18-55 years, were recruited at the Radboudumc in Nijmegen, the Netherlands. Participants received four intramuscular vaccinations on days 0, 28, 56 and 168 with either 30 µg or 100 µg of R0.6C and were randomised for the allocation of one of the two different adjuvant combinations: aluminium hydroxide alone, or aluminium hydroxide combined with Matrix-M1™ adjuvant. Adverse events were recorded from inclusion until 84 days after the fourth vaccination. Anti-R0.6C and anti-6C IgG titres were measured by enzyme-linked immunosorbent assay. Transmission-reducing activity of participants' serum and purified vaccine-specific immunoglobulin G was assessed by standard membrane feeding assays using laboratory-reared Anopheles stephensi mosquitoes and cultured P. falciparum gametocytes. RESULTS: Thirty-one participants completed four vaccinations and were included in the analysis. Administration of all doses was safe and well-tolerated, with one related grade 3 adverse event (transient fever) and no serious adverse events occurring. Anti-R0.6C and anti-6C IgG titres were similar between the 30 and 100 µg R0.6C arms, but higher in Matrix-M1™ arms. Neat participant sera did not induce significant transmission-reducing activity in mosquito feeding experiments, but concentrated vaccine-specific IgGs purified from sera collected two weeks after the fourth vaccination achieved up to 99% transmission-reducing activity. CONCLUSIONS: R0.6C/aluminium hydroxide with or without Matrix-M1™ is safe, immunogenic and induces functional Pfs48/45-specific transmission-blocking antibodies, albeit at insufficient serum concentrations to result in transmission reduction by neat serum. Future work should focus on identifying alternative vaccine formulations or regimens that enhance functional antibody responses. TRIAL REGISTRATION: The trial is registered with ClinicalTrials.gov under identifier NCT04862416.

A phase 1 study of the safety, reactogenicity, and immunogenicity of a Schistosoma mansoni vaccine with or without glucopyranosyl lipid A aqueous formulation (GLA-AF) in healthy adults from a non-endemic area.

BACKGROUND: Schistosomiasis caused by Schistosoma mansoni (Sm) is a chronic, debilitating and potentially deadly neglected tropical disease. The licensure of a vaccine to prevent schistosomiasis would represent a major breakthrough in public health. METHODS: The safety and immunogenicity of a candidate Sm vaccine were assessed in this phase I, double-blind, dose-escalation trial. Seventy-two healthy Sm-naïve 18-50 year olds were randomized to receive 3 doses ∼ 8 weeks apart of saline placebo, or 10 µg, 30 µg, or 100 µg of recombinant Sm-Tetraspanin-2 vaccine formulated on aluminum hydroxide adjuvant (Sm-TSP-2/Al) with or without 5 µg of glucopyranosyl lipid A aqueous formulation (GLA-AF). Clinical and serologic responses were assessed for 1 year after dose 3. RESULTS: Vaccines were safe and well-tolerated. The most common reactions were injection site tenderness and pain, and headache and fatigue. Tenderness and pain were more frequent in groups receiving vaccine with GLA-AF than placebo (p = 0.0036 and p = 0.0014, respectively). Injection site reactions among those given Sm-TSP-2/Al with GLA-AF lasted 1.22 and 1.33 days longer than those receiving Sm-TSP-2/Al without GLA-AF or placebo (p < 0.001 for both). Dose- and adjuvant-related increases in serum IgG against Sm-TSP-2 were observed. Peak IgG levels occurred 14 days after dose 3. Seroresponse frequencies were low among recipients of Sm-TSP-2/Al without GLA-AF, but higher among subjects receiving 30 µg or 100 µg of Sm-TSP-2/Al with GLA-AF. More seroresponses were observed among those given 30 µg or 100 µg of Sm-TSP-2/Al with GLA-AF compared to placebo (p = 0.023 and p < 0.001, respectively). Seroresponse frequencies were 0%, 30%, 50%, and 89%, respectively, among those given placebo, or 10 µg, 30 µg or 100 µg of Sm-TSP-2/Al with GLA-AF, suggesting a dose-response relationship for Sm-TSP-2/Al with GLA-AF (p = 0.0001). CONCLUSIONS: Sm-TSP-2/Al with or without GLA-AF was safe and well tolerated in a Sm-naïve population. A vaccine like the one under development may represent our best hope to eliminating this neglected tropical disease.

Expression, immunogenicity, histopathology, and potency of a mosquito-based malaria transmission-blocking recombinant vaccine.

Vaccines have been at the forefront of global research efforts to combat malaria, yet despite several vaccine candidates, this goal has yet to be realized. A potentially effective approach to disrupting the spread of malaria is the use of transmission-blocking vaccines (TBV), which prevent the development of malarial parasites within their mosquito vector, thereby abrogating the cascade of secondary infections in humans. Since malaria is transmitted to human hosts by the bite of an obligate insect vector, mosquito species in the genus Anopheles, targeting mosquito midgut antigens that serve as ligands for Plasmodium parasites represents a promising approach to breaking the transmission cycle. The midgut-specific anopheline alanyl aminopeptidase N (AnAPN1) is highly conserved across Anopheles vectors and is a putative ligand for Plasmodium ookinete invasion. We have developed a scalable, high-yield Escherichia coli expression and purification platform for the recombinant AnAPN1 TBV antigen and report on its marked vaccine potency and immunogenicity, its capacity for eliciting transmission-blocking antibodies, and its apparent lack of immunization-associated histopathologies in a small-animal model.