•Post-marketing surveillance is essential to monitor COVID-19 vaccine safety patterns.•Spontaneous reporting shows a comparable reporting pattern for basic and booster vaccines.•Spontaneous reporting ...shows similar reporting patterns for heterologous vaccination sequences.
The rapid roll-out of novel COVID-19 vaccines made near real-time post-marketing safety surveillance essential to identify rare and long-term adverse events following immunization (AEFIs). In light of the ongoing booster vaccination campaigns, it is key to monitor changes in observed safety patterns post-vaccination. The effect of sequential COVID-19 vaccinations, as well as heterologous vaccination sequences, on the observed post-vaccination safety pattern, remains largely unknown.
The primary objective of this study was to describe the profile of spontaneously reported AEFIs following COVID-19 vaccination in the Netherlands, including the primary and booster series. Reports from consumers and healthcare professionals were collected via a COVID-19 vaccine-tailored online reporting form by the National Pharmacovigilance Centre Lareb (Lareb) between 6 January 2021 and 31 August 2022. The data were used to describe the most frequently reported AEFIs per vaccination moment, the consumer experienced burden per AEFI, and differences in AEFIs reported for homologous and heterologous vaccination sequences.
Lareb received 227,884 spontaneous reports over a period of twenty months. Overall, a high degree of similarity in local and systemic AEFIs per vaccination moment was observed, with no apparent change in the number of reports of serious adverse events after multiple COVID-19 vaccinations. No differences in the pattern of reported AEFIs per vaccination sequence was observed.
Spontaneous reported AEFIs demonstrated a similar reporting pattern for homologous and heterologous primary and booster series of COVID-19 vaccination in the Netherlands.
Abstract
Transmission-blocking interventions can play an important role in combating malaria worldwide. Recently, a highly potent Plasmodium falciparum transmission-blocking monoclonal antibody ...(TB31F) was demonstrated to be safe and efficacious in malaria-naive volunteers. Here we predict the potential public health impact of large-scale implementation of TB31F alongside existing interventions. We developed a pharmaco-epidemiological model, tailored to 2 settings of differing transmission intensity with already established insecticide-treated nets and seasonal malaria chemoprevention interventions. Community-wide annual administration (at 80% coverage) of TB31F over a 3-year period was predicted to reduce clinical incidence by 54% (381 cases averted per 1000 people per year) in a high-transmission seasonal setting, and 74% (157 cases averted per 1000 people per year) in a low-transmission seasonal setting. Targeting school-aged children gave the largest reduction in terms of cases averted per dose. An annual administration of the transmission-blocking monoclonal antibody TB31F may be an effective intervention against malaria in seasonal malaria settings.
Monoclonal antibodies could become a valuable tool against malaria. Here we utilized results from the first-in-human study for a transmission-blocking monoclonal antibody to predict its potential public health impact. We also identified age groups to prioritize with this intervention.
Malaria elimination requires interruption of the highly efficient transmission of Plasmodium parasites by mosquitoes. TB31F is a humanised monoclonal antibody that binds the gamete surface protein ...Pfs48/45 and inhibits fertilisation, thereby preventing further parasite development in the mosquito midgut and onward transmission. We aimed to evaluate the safety and efficacy of TB31F in malaria-naive participants.
In this open-label, first-in-human, dose-escalation, phase 1 clinical trial, healthy, malaria-naive, adult participants were administered a single intravenous dose of 0·1, 1, 3, or 10 mg/kg TB31F or a subcutaneous dose of 100 mg TB31F, and monitored until day 84 after administration at a single centre in the Netherlands. The primary outcome was the frequency and magnitude of adverse events. Additionally, TB31F serum concentrations were measured by ELISA. Transmission-reducing activity (TRA) of participant sera was assessed by standard membrane feeding assays with Anopheles stephensi mosquitoes and cultured Plasmodium falciparum gametocytes. The trial is registered with Clinicaltrials.gov, NCT04238689.
Between Feb 17 and Dec 10, 2020, 25 participants were enrolled and sequentially assigned to each dose (n=5 per group). No serious or severe adverse events occurred. In total, 33 grade 1 and six grade 2 related adverse events occurred in 20 (80%) of 25 participants across all groups. Serum of all participants administered 1 mg/kg, 3 mg/kg, or 10 mg/kg TB31F intravenously had more than 80% TRA for 28 days or more, 56 days or more, and 84 days or more, respectively. The TB31F serum concentration reaching 80% TRA was 2·1 μg/mL (95% CI 1·9–2·3). Extrapolating the duration of TRA from antibody kinetics suggests more than 80% TRA is maintained for 160 days (95% CI 136–193) following a single intravenous 10 mg/kg dose.
TB31F is a well tolerated and highly potent monoclonal antibody capable of completely blocking transmission of P falciparum parasites from humans to mosquitoes. In areas of seasonal transmission, a single dose might cover an entire malaria season.
PATH's Malaria Vaccine Initiative.
Whole sporozoite immunization under chemoprophylaxis (CPS regime) induces long-lasting sterile homologous protection in the controlled human malaria infection model using Plasmodium falciparum strain ...NF54. The relative proficiency of liver-stage parasite development may be an important factor determining immunization efficacy. Previous studies show that Plasmodium falciparum strain NF135 produces relatively high numbers of large liver-stage schizonts in vitro. Here, we evaluate this strain for use in CPS immunization regimes.
In a partially randomized, open-label study conducted at the Radboudumc, Nijmegen, the Netherlands, healthy, malaria-naïve adults were immunized by three rounds of fifteen or five NF135-infected mosquito bites under mefloquine prophylaxis (cohort A) or fifteen NF135-infected mosquito bites and presumptive treatment with artemether/lumefantrine (cohort B). Cohort A participants were exposed to a homologous challenge 19 weeks after immunization. The primary objective of the study was to evaluate the safety and tolerability of CPS immunizations with NF135.
Relatively high liver-to-blood inocula were observed during immunization with NF135 in both cohorts. Eighteen of 30 (60%) high-dose participants and 3/10 (30%) low-dose participants experienced grade 3 adverse events 7 to 21 days following their first immunization. All cohort A participants and two participants in cohort B developed breakthrough blood-stage malaria infections during immunizations requiring rescue treatment. The resulting compromised immunizations induced modest sterile protection against homologous challenge in cohort A (5/17; 29%).
These CPS regimes using NF135 were relatively poorly tolerated and frequently required rescue treatment, thereby compromising immunization efficiency and protective efficacy. Consequently, the full potential of NF135 sporozoites for induction of immune protection remains inconclusive. Nonetheless, the high liver-stage burden achieved by this strain highlights it as an interesting potential candidate for novel whole sporozoite immunization approaches.
The trial was registered at ClinicalTrials.gov under identifier NCT03813108.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
During co-evolution
parasites and vertebrates went through a process of selection resulting in defined and preferred parasite-host combinations. As such,
) sporozoites can infect human hepatocytes ...while seemingly incompatible with host cellular machinery of other species. The compatibility between parasite invasion ligands and their respective human hepatocyte receptors plays a key role in
host selectivity. However, it is unclear whether the ability of
sporozoites to mature in cross-species infection also plays a role in host tropism. Here we used fresh hepatocytes isolated from porcine livers to study permissiveness to
sporozoite invasion and development. We monitored intra-hepatic development
immunofluorescence using anti-HSP70, MSP1, EXP1, and EXP2 antibodies. Our data shows that
sporozoites can invade non-human hepatocytes and undergo partial maturation with a significant decrease in schizont numbers between day three and day five. A possible explanation is that
sporozoites fail to form a parasitophorous vacuolar membrane (PVM) during invasion. Indeed, the observed aberrant EXP1 and EXP2 staining supports the presence of an atypical PVM. Functions of the PVM include the transport of nutrients, export of waste, and offering a protective barrier against intracellular host effectors. Therefore, an atypical PVM likely results in deficiencies that may detrimentally impact parasite development at multiple levels. In summary, despite successful invasion of porcine hepatocytes,
development arrests at mid-stage, possibly due to an inability to mobilize critical nutrients across the PVM. These findings underscore the potential of a porcine liver model for understanding the importance of host factors required for
mid-liver stage development.
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