Progress in Immunization Safety Monitoring - Worldwide, 2020-2022.

Effective surveillance of adverse events following immunization (AEFIs) primarily relies on the collaboration of two partners: national regulatory authorities (NRAs) and national expanded programs on immunization (EPIs). In December 2020, the World Health Organization (WHO) Global Advisory Committee for Vaccine Safety recommended a new case-based indicator of national capacity to monitor immunization safety: at least one serious AEFI reported per 1 million total population per year. To achieve this indicator, WHO-affiliated countries and territories (WHO countries) rely upon data generated from functional AEFI surveillance systems. This report describes 2020-2022 global, regional, and national progress in use of the newly introduced immunization safety monitoring indicator and progress on joint AEFI reporting from national EPIs and NRAs. Among WHO countries, 51 (24%) of 214 implemented the new indicator in 2020, 111 (52%) of 214 implemented it in 2021, and 92 (43%) of 215 in 2022. In 2020, 41 (19%) WHO countries reported AEFI data jointly from EPIs and NRAs; this increased to 55 (26%) in 2021 and 57 (27%) in 2022. These findings, resulting in part from the intensified support for COVID-19 vaccination, demonstrate that national AEFI surveillance systems increasingly support the timely use and sharing of case-based immunization safety data, but work is still needed to strengthen global vaccine safety monitoring.

5-Hydroxy-L-[beta-11C]tryptophan versus alpha-[11C]methyl-L-tryptophan for positron emission tomography imaging of serotonin synthesis capacity in the rhesus monkey brain.

The purpose of this study was to compare two positron emission tomography (PET) tracers that were developed to follow serotonin (5HT) synthesis by performing sequential PET scanning of the same rhesus monkey (n=4) on the same day. alpha-[11C]Methyl-L-tryptophan ([11C]AMT) and 5-Hydroxy-L-[beta-11C]tryptophan ([11C]HTP) are substrates in the first and second enzymatic steps, respectively, in the biosynthesis of 5HT. Regional net accumulation rate constants were derived from kinetic (two-tissue compartment model with irreversible tracer trapping) and graphic (Patlak) analyses, using the arterial plasma concentrations as input. The kinetic data analysis showed that the rate constant for the transfer of [11C]HTP into the brain (K1) was higher than that for [11C]AMT in the striatum and thalamus but was similar in other brain regions. The rate constant for tracer trapping (k3) was also higher for [11C]HTP than for [11C]AMT in the striatum (0.046+/-0.024 versus 0.019+/-0.006 min(-1)) and thalamus (0.039+/-0.013 versus 0.016+/-0.007 min(-1)). In agreement with previously reported regional HTP accumulation rates, the net accumulation rate constant (K(acc)) for [11C]HTP was also higher in these regions than in other brain regions; this is in contrast to the uniform distribution of [11C]AMT K(acc) values. This suggests that the regional net accumulation rates obtained with these two PET tracers will be of different magnitude, which might be related to the activity of each targeted enzyme.

Potential of [11C]DASB for measuring endogenous serotonin with PET: binding studies.

The serotonin transporter radioligand [11C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile, or [11C]DASB, was examined in order to assess its potential for measuring fluctuations in endogenous serotonin concentrations with positron emission tomography. Binding characteristics of [11C]DASB and the propensity for serotonin to displace the tracer were explored in rat brain homogenates. Experiments showed that serotonin displaced [11C]DASB in vitro. Ex vivo experiments performed after tranylcypromine injection (3 or 15 mg/kg) showed a dose-dependent trend in radioactivity uptake and suggested that serotonin may compete with [11C]DASB for transporter binding.

Effect on [11C]DASB binding after tranylcypromine-induced increase in serotonin concentration: positron emission tomography studies in monkeys and rats.

Several research groups have demonstrated that under specific conditions, in vivo neuroreceptor binding techniques can be used to measure acute changes in the concentrations of endogenous transmitters in the vicinity of neuroreceptors. The aim of this study was to investigate whether [(11)C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile ([(11)C]DASB) binding to the plasma membrane serotonin transporter (SERT) in the rhesus monkey and rat brain decreased after a pharmacologically-induced increase in the interstitial serotonin (5HT) concentration. Three rhesus monkeys were given repeated single boluses of [(11)C]DASB in sequential positron emission tomography (PET) experiments. Rats were given the tracer as a bolus dose plus a constant infusion. In vivo binding in both models was studied before and after presumably having increased interstitial 5HT concentrations using tranylcypromine (TCP), which inhibits the enzyme (monoamine oxidase, MAO), that degrades 5HT. The rat brain tissue was analyzed using high-performance liquid chromatography (HPLC) to determine the proportion of the PET signal comprising unchanged [(11)C]DASB. The binding of [(11)C]DASB in the thalamus decreased in both rhesus monkeys and rats after TCP administration. The possibility of using [(11)C]DASB as a tool for monitoring changes in endogenous serotonin concentrations merits further investigation.

Validation studies on the 5-hydroxy-L-[beta-11C]-tryptophan/PET method for probing the decarboxylase step in serotonin synthesis.

The two-tissue compartment model, including irreversible trapping in the second compartment (2TCM) is used to describe the kinetics of 5-Hydroxy-L-[beta-(11)C]-tryptophan ([(11)C]HTP), a radioligand used in positron emission tomography (PET) for probing the second enzymatic step in the biosynthesis of serotonin. In this study, we examined the capacity of the model to track pharmacological changes in this biological process. We also investigated the potential loss of [(11)C]HTP-derived radioactivity during a PET study, since loss should be negligible not to alter quantification. Six rhesus monkeys were investigated using bolus [(11)C]HTP/PET methodology before and after pharmacological intervention. The second enzymatic step in serotonin synthesis was inhibited using the aromatic L-amino acid decarboxylase inhibitor NSD1015 (10 mg/kg). The extent of [(11)C]-derived radioactivity loss from the brain was studied by inhibition of the enzyme responsible for formation of the tissue metabolite, monoamine oxidase A, using clorgyline (2 mg/kg). After NSD1015, the uptake of [(11)C]HTP-derived radioactivity was increased in all the investigated brain regions, while the parameter used to reflect decarboxylase activity, the net accumulation rate constant (K(acc)), was decreased by 37% in the striatum, compared with baseline. Pretreatment with clorgyline did not change the brain uptake of [(11)C]HTP-derived radioactivity or K(acc). This study demonstrates that the 2TCM for [(11)C]HTP/PET is able to detect changes occurring during alteration of the biological process (i.e., the conversion of HTP to serotonin). Elimination of the radiotracer metabolite [(11)C]HIAA from the brain may be considered negligible if the PET study is limited to 60 min.