Development of standardized laboratory methods and quality processes for a phase III study of the RTS, S/AS01 candidate malaria vaccine

BACKGROUND\ud \ud A pivotal phase III study of the RTS,S/AS01 malaria candidate vaccine is ongoing in several research centres across Africa. The development and establishment of quality systems was a requirement for trial conduct to meet international regulatory standards, as well as providing an important capacity strengthening opportunity for study centres.\ud \ud METHODS\ud \ud Standardized laboratory methods and quality assurance processes were implemented at each of the study centres, facilitated by funding partners.\ud \ud RESULTS\ud \ud A robust protocol for determination of parasite density based on actual blood cell counts was set up in accordance with World Health Organization recommendations. Automated equipment including haematology and biochemistry analyzers were put in place with standard methods for bedside testing of glycaemia, base excess and lactacidaemia. Facilities for X-rays and basic microbiology testing were also provided or upgraded alongside health care infrastructure in some centres. External quality assurance assessment of all major laboratory methods was established and method qualification by each laboratory demonstrated. The resulting capacity strengthening has ensured laboratory evaluations are conducted locally to the high standards required in clinical trials.\ud \ud CONCLUSION\ud \ud Major efforts by study centres, together with support from collaborating parties, have allowed standardized methods and robust quality assurance processes to be put in place for the phase III evaluation of the RTS, S/AS01 malaria candidate vaccine. Extensive training programmes, coupled with continuous commitment from research centre staff, have been the key elements behind the successful implementation of quality processes. It is expected these activities will culminate in healthcare benefits for the subjects and communities participating in these trials.\ud \ud TRIAL REGISTRATION\ud \ud Clinicaltrials.gov NCT00866619

Propagation or failure of detonation across an air gap in an LX-17 column: continuous time-dependent detonation or shock speed using the Embedded Fiber Optic (EFO) technique

The detailed history of the shock/detonation wave propagation after crossing a room-temperature-room-pressure (RTP) air gap between a 25.4 mm diameter LX-17 donor column and a 25.4 mm diameter by 25.4 mm long LX-17 acceptor pellet is investigated for three different gap widths (3.07, 2.08, and 0.00 mm) using the Embedded Fiber Optic (EFO) technique. The 2.08 mm gap propagated and the 3.07 mm gap failed and this can be seen clearly and unambiguously in the EFO data even though the 25.4 mm-long acceptor pellet would be considered quite short for a determination by more traditional means such as pins

Evaluation of the Safety and Immunogenicity of the RTS,S/AS01E Malaria Candidate Vaccine When Integrated in the Expanded Program of Immunization

Background. The RTS,S/AS01E malaria candidate vaccine is being developed for immunization of African infants through the Expanded Program of Immunization (EPI). Methods. This phase 2, randomized, open, controlled trial conducted in Ghana, Tanzania, and Gabon evaluated the safety and immunogenicity of RTS,S/AS01E when coadministered with EPI vaccines. Five hundred eleven infants were randomized to receive RTS,S/AS01E at 0, 1, and 2 months (in 3 doses with diphtheria, tetanus, and wholecell pertussis conjugate [DTPw]; hepatitis B [HepB]; Haemophilus influenzae type b [Hib]; and oral polio vaccine [OPV]), RTS,S/AS01E at 0, 1, and 7 months (2 doses with DTPwHepB/Hib+OPV and 1 dose with measles and yellow fever), or EPI vaccines only. Results. The occurrences of serious adverse events were balanced across groups; none were vaccine-related. One child from the control group died. Mild to moderate fever and diaper dermatitis occurred more frequently in the RTS,S/AS01E coadministration groups. RTS,S/AS01E generated high anti-circumsporozoite protein and anti- hepatitis B surface antigen antibody levels. Regarding EPI vaccine responses upon coadministration when considering both immunization schedules, despite a tendency toward lower geometric mean titers to some EPI antigens, predefined noninferiority criteria were met for all EPI antigens except for polio 3 when EPI vaccines were given with RTS,S/AS01E at 0, 1, and 2 months. However, when antibody levels at screening were taken into account, the rates of response to polio 3 antigens were comparable between groups. Conclusion. RTS,S/AS01E integrated in the EPI showed a favorable safety and immunogenicity evaluation. Trial registration. ClinicalTrials.gov identifier: NCT00436007. GlaxoSmithKline study ID number: 106369 (Malaria-050

Correlates of protection against symptomatic and asymptomatic SARS-CoV-2 infection

The global supply of COVID-19 vaccines remains limited. An understanding of the immune response that is predictive of protection could facilitate rapid licensure of new vaccines. Data from a randomized efficacy trial of the ChAdOx1 nCoV-19 (AZD1222) vaccine in the United Kingdom was analyzed to determine the antibody levels associated with protection against SARS-CoV-2. Binding and neutralizing antibodies at 28 days after the second dose were measured in infected and noninfected vaccine recipients. Higher levels of all immune markers were correlated with a reduced risk of symptomatic infection. A vaccine efficacy of 80% against symptomatic infection with majority Alpha (B.1.1.7) variant of SARS-CoV-2 was achieved with 264 (95% CI: 108, 806) binding antibody units (BAU)/ml: and 506 (95% CI: 135, not computed (beyond data range) (NC)) BAU/ml for anti-spike and anti-RBD antibodies, and 26 (95% CI: NC, NC) international unit (IU)/ml and 247 (95% CI: 101, NC) normalized neutralization titers (NF50) for pseudovirus and live-virus neutralization, respectively. Immune markers were not correlated with asymptomatic infections at the 5% significance level. These data can be used to bridge to new populations using validated assays, and allow extrapolation of efficacy estimates to new COVID-19 vaccines

νi13/2 structures in 155Sm and 159Gd: Supporting evidence of a Z=60 deformed subshell gap

Maximal ground-state deformation should occur when both proton and neutron Fermi surfaces are located at midshell. However, subshell gaps that stabilize large deformation can exist at proton or neutron values other than midshell. One such gap may occur at Z=60 in the rare-earth region, as the energy of the first 2+ states in even-even nuclei are often lowest in an isotonic chain for neodymium (Z=60) rather than the midshell isotopes of dysprosium (Z=66). Further evidence of this deformed gap has now been observed by investigating the signature splitting systematics of the νi13/2 bands found in the odd-N, rare-earth nuclei. These were aided by the present observation of the νi13/2 band in Gd159 and the confirmation of the same structure in Sm155 via the transfer of a neutron from a Gd160 beam to a Sm154 target

Induction of Plasmodium falciparum-Specific CD4+ T Cells and Memory B Cells in Gabonese Children Vaccinated with RTS,S/AS01E and RTS,S/AS02D

The recombinant circumsporozoite protein (CS) based vaccine, RTS,S, confers protection against Plasmodium falciparum infection in controlled challenge trials and in field studies. The RTS,S recombinant antigen has been formulated with two adjuvant systems, AS01 and AS02, which have both been shown to induce strong specific antibody responses and CD4 T cell responses in adults. As infants and young children are particularly susceptible to malaria infection and constitute the main target population for a malaria vaccine, we have evaluated the induction of adaptive immune responses in young children living in malaria endemic regions following vaccination with RTS,S/AS01(E) and RTS,S/AS02(D). Our data show that a CS-specific memory B cell response is induced one month after the second and third vaccine dose and that CS-specific antibodies and memory B cells persist up to 12 months after the last vaccine injection. Both formulations also induced low but significant amounts of CS-specific IL-2(+) CD4(+) T cells one month after the second and third vaccine dose, upon short-term in vitro stimulation of whole blood cells with peptides covering the entire CS derived sequence in RTS,S. These results provide evidence that both RTS,S/AS01(E) and RTS,S/AS02(D) induced adaptive immune responses including antibodies, circulating memory B cells and CD4(+) T cells directed against P. falciparum CS protein.ClinicalTrials.gov NCT00307021

Possible quenching of static neutron pairing near the N=98 deformed shell gap: Rotational structures in Gd-160,Gd-161

A Gd160 beam was accelerated to an energy of 1000 MeV and, separately, bombarded thick targets of Sm154 and Dy164 in order to observe neutron-rich, rare-earth nuclei via deep-inelastic collision processes. Gammasphere was utilized to observe ?-ray emissions. Many new states and transitions were observed in Gd160 as a result of so-called unsafe Coulomb excitation. The ground-state band in Gd160 has been extended to Ip=20+ and a rotational band based on the Kp=4+ state, previously associated with a hexadecapole vibration, was observed up to 18+. The quasiparticle configuration of the Kp=4+ band has been determined, and its unusual alignment behavior may result from a possible quenching of static neutron pairing. In addition, the band based on the [523]5/2 quasineutron orbital in Gd161 was extended from 11/2- to 33/2- and also displays the same unusual alignment behavior

Possible quenching of static neutron pairing near the N=98 deformed shell gap: Rotational structures in Gd 160,161

A Gd160 beam was accelerated to an energy of 1000 MeV and, separately, bombarded thick targets of Sm154 and Dy164 in order to observe neutron-rich, rare-earth nuclei via deep-inelastic collision processes. Gammasphere was utilized to observe ?-ray emissions. Many new states and transitions were observed in Gd160 as a result of so-called unsafe Coulomb excitation. The ground-state band in Gd160 has been extended to Ip=20+ and a rotational band based on the Kp=4+ state, previously associated with a hexadecapole vibration, was observed up to 18+. The quasiparticle configuration of the Kp=4+ band has been determined, and its unusual alignment behavior may result from a possible quenching of static neutron pairing. In addition, the band based on the [523]5/2 quasineutron orbital in Gd161 was extended from 11/2- to 33/2- and also displays the same unusual alignment behavior