Showing papers by "Angela M. Minassian published in 2023"
TL;DR: In this paper , a Phase 1b, single-center, dose-escalation, age deescalation and double-blind, randomized, controlled trial was conducted in Bagamoyo, Tanzania, where healthy adults (18-35 years), young children (1-6 years) and infants (6-11 months) were recruited to receive a priming dose of viral-vectored ChAd63 RH5 followed by a booster dose of MVA RH5 (or rabies control vaccine) 8 weeks later.
Abstract: Background RH5 is the leading blood-stage candidate antigen for inclusion in a Plasmodium falciparum malaria vaccine, however, its safety profile and ability to induce functional immune responses in a malaria-endemic population are unknown. Characterising safety and immunogenicity is key to refine and progress next-generation RH5-based blood-stage malaria vaccines to field efficacy assessment. Methods A Phase 1b, single-center, dose-escalation, age de-escalation, double-blind, randomized, controlled trial was conducted in Bagamoyo, Tanzania. Healthy adults (18-35 years), young children (1-6 years) and infants (6-11 months) were recruited to receive a priming dose of viral-vectored ChAd63 RH5 (or rabies control vaccine) followed by a booster dose of MVA RH5 (or rabies control vaccine) 8 weeks later. The primary outcomes were the number of solicited and unsolicited adverse events following vaccination and the number of serious adverse events over the whole study period. Secondary outcomes included quantitative and qualitative measures of the anti-RH5 immune response. All participants receiving at least one dose of vaccine were included in the primary analyses. Findings Between 12th April and 25th October 2018 a total of 63 adults, children and infants were recruited and primed and 60 of these were boosted, all completing six months of follow-up post-priming vaccination. Vaccinations were well-tolerated with participants reporting predominantly mild reactogenicity, with profiles comparable between ChAd63 RH5, MVA RH5 and rabies vaccine groups, and across the age groups. No serious adverse events were reported during the study period. RH5-specific T cell, B cell and serum antibody responses were induced by vaccination. Higher anti-RH5 serum IgG responses were observed post-boost in the 1-6 year old children (median 93 microgram/mL; range: 31-508 microgram/mL) and infants (median 149 microgram/mL; range: 29-352 microgram/mL) as compared to adults (median 14 microgram/mL; range: 9-15 microgram/mL). These contracted over time post-boost, but the same hierarchy of responses across the age groups was maintained to end of follow-up at 16 weeks post-boost (day 168). Vaccine-induced anti-RH5 antibodies were functional showing growth inhibition activity (GIA) in vitro against P. falciparum blood-stage parasites. The highest levels were observed in the 6-11 month old infants, with 6/11 showing >60% GIA following dilution of total IgG to 2.5 mg/mL (median 61%; range: 41-78%). Interpretation The ChAd63-MVA RH5 vaccine regimen shows an acceptable safety and reactogenicity profile and encouraging immunogenicity in children and infants residing in a malaria-endemic area. The levels of functional GIA observed in the RH5 vaccinated 6-11 month old infants are the highest levels reported to-date following human vaccination. These data support onward clinical development of RH5-based blood-stage vaccines that aim to protect against clinical malaria in young African infants. Funding Medical Research Council, London, United Kingdom. Trial Registration ISRCTN registry: 47448832 and ClinicalTrials.gov: NCT03435874.
2 citations
TL;DR: The COV-BOOST trial as mentioned in this paper compared the immunogenicity and kinetics of responses to third doses of vaccines from day (D) 28 to D242 following third doses in seven study arms.
2 citations
TL;DR: The first study to investigate the reactogenicity and immunogenicity of COVID-19 vaccine regimens in adolescents was conducted in this article , where a phase II, single-blind, multi-centre, randomised-controlled trial recruited across seven UK sites from September to November 2021, with follow-up visits to August 2022.
1 citations
TL;DR: In this paper , a linear model fit was conducted including donor (source of RBC) and day of GIA as independent variables to evaluate sources of EoA in % inhibition in GIA (%GIA), and the impact of repeat assays on 95% confidence interval (95%CI) of these readouts was estimated.
Abstract: For blood-stage malaria vaccine development, the in vitro growth inhibition assay (GIA) has been widely used to evaluate functionality of vaccine-induced antibodies (Ab), and Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) is a leading blood-stage antigen. However, precision, also called "error of assay (EoA)", in GIA readouts and the source of EoA has not been evaluated systematically.In the Main GIA experiment, 4 different cultures of P. falciparum 3D7 parasites were prepared with red blood cells (RBC) collected from 4 different donors. For each culture, 7 different anti-RH5 Ab (either monoclonal or polyclonal Ab) were tested by GIA at two concentrations on three different days (168 data points). To evaluate sources of EoA in % inhibition in GIA (%GIA), a linear model fit was conducted including donor (source of RBC) and day of GIA as independent variables. In addition, 180 human anti-RH5 polyclonal Ab were tested in a Clinical GIA experiment, where each Ab was tested at multiple concentrations in at least 3 independent GIAs using different RBCs (5,093 data points). The standard deviation (sd) in %GIA and in GIA50 (Ab concentration that gave 50%GIA) readouts, and impact of repeat assays on 95% confidence interval (95%CI) of these readouts was estimated.The Main GIA experiment revealed that the RBC donor effect was much larger than the day effect, and an obvious donor effect was also observed in the Clinical GIA experiment. Both %GIA and log-transformed GIA50 data reasonably fit a constant sd model, and sd of %GIA and log-transformed GIA50 measurements were calculated as 7.54 and 0.206, respectively. Taking the average of three repeat assays (using three different RBCs) reduces the 95%CI width in %GIA or in GIA50 measurements by ~ half compared to a single assay.The RBC donor effect (donor-to-donor variance on the same day) in GIA was much bigger than the day effect (day-to-day variance using the same donor's RBC) at least for the RH5 Ab evaluated in this study; thus, future GIA studies should consider the donor effect. In addition, the 95%CI for %GIA and GIA50 shown here help when comparing GIA results from different samples/groups/studies; therefore, this study supports future malaria blood-stage vaccine development.
TL;DR: Hou et al. as discussed by the authors conducted two phase 1/2a clinical trials to assess two vaccines targeting P. vivax Duffy-binding protein region II (PvDBPII).
Abstract: There are no licensed vaccines against Plasmodium vivax. We conducted two phase 1/2a clinical trials to assess two vaccines targeting P. vivax Duffy-binding protein region II (PvDBPII). Recombinant viral vaccines using chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) vectors as well as a protein and adjuvant formulation (PvDBPII/Matrix-M) were tested in both a standard and a delayed dosing regimen. Volunteers underwent controlled human malaria infection (CHMI) after their last vaccination, alongside unvaccinated controls. Efficacy was assessed by comparisons of parasite multiplication rates in the blood. PvDBPII/Matrix-M, given in a delayed dosing regimen, elicited the highest antibody responses and reduced the mean parasite multiplication rate after CHMI by 51% (n = 6) compared with unvaccinated controls (n = 13), whereas no other vaccine or regimen affected parasite growth. Both viral-vectored and protein vaccines were well tolerated and elicited expected, short-lived adverse events. Together, these results support further clinical evaluation of the PvDBPII/Matrix-M P. vivax vaccine. Description The PvDBPII/Matrix-M vaccine, which targets the Plasmodium vivax Duffy-binding protein, reduced growth of malaria parasites in blood of humans. Editor’s summary Plasmodium vivax is the second most common cause of malaria in humans and currently lacks an effective vaccine. Here, Hou et al. report encouraging clinical trial results testing the safety and efficacy of two vaccine candidates, both based on the P. vivax Duffy-binding protein region II (PvDBPII). One of the vaccine candidates, an adjuvanted PvDBPII protein vaccine, elicited the strongest antibody responses, particularly when delivered in a delayed dosing regimen. This correlated with the superior control of parasitemia when vaccinees underwent a controlled human malaria infection. These data, plus a favorable safety profile, support further clinical testing of this vaccine regimen. —Courtney Malo
TL;DR: The challenges of using CHMI for P. vivax vaccine development and evaluation, lessons learned from previous and ongoing clinical trials, and the way forward to effectively perform PvCHMI to support vaccine development, are discussed in this paper .
Abstract: Controlled Human Malaria Infection models (CHMI) have been critical to advancing new vaccines for malaria. Stringent and safe preparation of a challenge agent is key to the success of any CHMI. Difficulty producing the Plasmodium vivax parasite in vitro has limited production of qualified parasites for CHMI as well as the functional assays required to screen and down-select candidate vaccines for this globally distributed parasite. This and other challenges to P. vivax CHMI (PvCHMI), including scientific, logistical, and ethical obstacles, are common to P. vivax research conducted in both non-endemic and endemic countries, with additional hurdles unique to each. The challenges of using CHMI for P. vivax vaccine development and evaluation, lessons learned from previous and ongoing clinical trials, and the way forward to effectively perform PvCHMI to support vaccine development, are discussed.