Biology subjects

Cowley, L. A.

Publications and source records attributed to Cowley, L. A..

2 recordsLinked to original sources

bioRxiv2024

Development of an improved blood-stage malaria vaccine targeting the essential RH5-CyRPA-RIPR invasion complex

In recent years, reticulocyte-binding protein homologue 5 (RH5) has emerged as a leading blood-stage Plasmodium falciparum malaria vaccine antigen. The most advanced blood-stage vaccine candidate in a Phase 2b clinical trial, RH5.1/Matrix-M, is based on a full-length soluble protein-with-adjuvant formulation. RH5 interacts with cysteine-rich protective antigen (CyRPA) and RH5- interacting protein (RIPR) to form an essential heterotrimeric "RCR-complex". Here, we investigated whether a vaccine candidate based on the ternary RCR-complex could substantially improve upon the leading clinical candidate RH5.1/Matrix-M in preclinical studies. Using a panel of monoclonal antibodies (mAbs) we confirm that parasite growth-inhibitory epitopes on each antigen are exposed on the surface of the RCR-complex and that mAb pairs binding to different antigens can function additively or synergistically to mediate parasite growth inhibition activity (GIA) in vitro. However, immunisation of rats with the RCR-complex consistently fails to outperform RH5.1 alone. We show this is due to immuno-dominance of RIPR coupled with the inferior potency of anti-full length RIPR polyclonal IgG antibodies as compared to the anti-RH5 and anti-CyRPA response. To address this, we identified the growth-inhibitory antibody epitopes of RIPR are clustered within C-terminal EGF-like domains of RIPR. A fusion of these EGF domains to CyRPA, called "R78C", combined with RH5.1, provided a new vaccination strategy that improves upon the levels of in vitro GIA seen with RH5.1 alone. Superiority of the combination antigen vaccine candidate was achieved by the induction of a quantitatively higher, but qualitatively similar, polyclonal antibody response that demonstrated additive GIA across the three antigen targets. These preclinical data justified the advancement of the RH5.1+R78C/Matrix-M combination vaccine to a Phase 1 clinical trial.

immunology↗

bioRxiv2018

Serotype association with neonatal invasive potential, disease manifestation, and clinical outcome in group B Streptococcus: A Bayesian analysis

BackgroundCase-carrier ratios quantifying the relative pathogenicity of serotypes can inform vaccine formulations for antigenically-diverse pathogens. However, sparse serotype-specific counts in epidemiologic datasets may undermine such analyses, most notably for rare serotypes that pose emergence risks in vaccinated populations. This challenge is well-illustrated in Group B streptococcus (GBS), where serotype III dominates in both carriage and disease.\n\nMethodsWe develop an empirical Bayes random-effects model based on conjugate Dirichlet-multinomial distributions of serotype frequencies in carriage and disease states. We validate the model using simulated datasets, and apply it to data from 15 paired sets of GBS isolates from intrapartum rectovaginal colonization (n=3403) and neonatal invasive disease (NID; n=1088), 16 from blood (n=2352) and cerebrospinal fluid (n=780) neonatal specimens, and 3 from fatal (n=173) and non-fatal (n=1684) neonatal invasive infections.\n\nResultsOur method accurately recovers parameters in simulated datasets. Using this approach, we confirm that GBS serotype III exhibits the greatest invasiveness, followed by serotype Ia with a 75.3% (95%CrI: 43.7-93.8%) lower estimate. Enhanced invasiveness of serotypes III and Ia is most evident in late-onset disease. Non-hexavalent-vaccine serotypes, which are rare in carriage and disease, generally show lower invasiveness; serotype IX/non-typeable GBS, the most prevalent cause of non-vaccine-preventable disease, is 98.7% (81.7-99.9%) and 94.2% (13.9-99.6%) less invasive than serotypes III and Ia, respectively.\n\nConclusionsWe present a strategy for measuring associations of serotype with carrier and disease states in the presence of sparse counts, avoiding biases that exist in common ad-hoc approaches.

epidemiology↗