The Origins and Risk Factors for Serotype-2 Vaccine-Derived Poliovirus Emergences in Africa During 2016-2019.

Serotype 2 oral poliovirus vaccine (OPV2) can revert to regain wild-type neurovirulence and spread to cause emergences of vaccine-derived poliovirus (VDPV2). After its global withdrawal from routine immunization in 2016, outbreak response use has created a cycle of VDPV2 emergences that threaten eradication. We implemented a hierarchical model based on VP1 region genetic divergence, time, and location to attribute emergences to campaigns and identify risk factors. We found that a 10 percentage point increase in population immunity in children younger than 5 years at the campaign time and location corresponds to a 18.0% decrease (95% credible interval [CrI], 6.3%-28%) in per-campaign relative risk, and that campaign size is associated with emergence risk (relative risk scaling with population size to a power of 0.80; 95% CrI, .50-1.10). Our results imply how Sabin OPV2 can be used alongside the genetically stable but supply-limited novel OPV2 (listed for emergency use in November 2020) to minimize emergence risk.

Src homology 2 domain containing protein 5 (SH2D5) binds the breakpoint cluster region protein, BCR, and regulates levels of Rac1-GTP.

SH2D5 is a mammalian-specific, uncharacterized adaptor-like protein that contains an N-terminal phosphotyrosine-binding domain and a C-terminal Src homology 2 (SH2) domain. We show that SH2D5 is highly enriched in adult mouse brain, particularly in Purkinjie cells in the cerebellum and the cornu ammonis of the hippocampus. Despite harboring two potential phosphotyrosine (Tyr(P)) recognition domains, SH2D5 binds minimally to Tyr(P) ligands, consistent with the absence of a conserved Tyr(P)-binding arginine residue in the SH2 domain. Immunoprecipitation coupled to mass spectrometry (IP-MS) from cultured cells revealed a prominent association of SH2D5 with breakpoint cluster region protein, a RacGAP that is also highly expressed in brain. This interaction occurred between the phosphotyrosine-binding domain of SH2D5 and an NxxF motif located within the N-terminal region of the breakpoint cluster region. siRNA-mediated depletion of SH2D5 in a neuroblastoma cell line, B35, induced a cell rounding phenotype correlated with low levels of activated Rac1-GTP, suggesting that SH2D5 affects Rac1-GTP levels. Taken together, our data provide the first characterization of the SH2D5 signaling protein.

Effectiveness of poliovirus vaccines against circulating vaccine-derived type 2 poliomyelitis in Nigeria between 2017 and 2022: a case-control study.

BACKGROUND: Between 2018 and 2022, Nigeria experienced continuous transmission of circulating vaccine-derived type 2 poliovirus (cVDPV2), with 526 cases of cVDPV2 poliomyelitis detected in total and approximately 180 million doses of monovalent type 2 oral poliovirus vaccine (mOPV2) and 450 million doses of novel type 2 oral poliovirus vaccine (nOPV2) delivered in outbreak response campaigns. Inactivated poliovirus vaccine (IPV) was introduced into routine immunisation in 2015, with a second dose added in 2021. We aimed to estimate the effectiveness of nOPV2 against cVDPV2 paralysis and compare nOPV2 effectiveness with that of mOPV2 and IPV. METHODS: In this retrospective case-control study, we used acute flaccid paralysis (AFP) surveillance data in Nigeria from Jan 1, 2017, to Dec 31, 2022, using age-matched, onset-matched, and location-matched cVDPV2-negative AFP cases as test-negative controls. We also did a parallel prospective study from March, 2021, using age-matched community controls from the same settlement as the cases. We included children born after May, 2016, younger than 60 months, for whom polio immunisation history (doses of OPV from campaigns and IPV) was reported. We estimated the per-dose effectiveness of nOPV2 against cVDPV2 paralysis using conditional logistic regression and compared nOPV2 effectiveness with that of mOPV2 and IPV. FINDINGS: In the retrospective case-control study, we identified 509 cVDPV2 poliomyelitis cases in Nigeria with case verification and paralysis onset between Jan 1, 2017, and Dec 31, 2022. Of these, 82 children were excluded for not meeting inclusion criteria, and 363 (85%) of 427 eligible cases were matched to 1303 test-negative controls. Cases reported fewer OPV and IPV doses than test-negative controls (mean number of OPV doses 5·9 [SD 4·2] in cases vs 6·7 [4·3] in controls; one or more IPV doses reported in 95 [26%] of 363 cases vs 513 [39%] of 1303 controls). We found low per-dose effectiveness of nOPV2 (12%, 95% CI -2 to 25) and mOPV2 (17%, 3 to 29), but no significant difference between the two vaccines (p=0·67). The estimated effectiveness of one IPV dose was 43% (23 to 58). In the prospective study, 181 (46%) of 392 eligible cases were matched to 1557 community controls. Using community controls, we found a high effectiveness of IPV (89%, 95% CI 83 to 93, for one dose), a low per-dose effectiveness of nOPV2 (-23%, -45 to -5) and mOPV2 (1%, -23 to 20), and no significant difference between the per-dose effectiveness of nOPV2 and mOPV2 (p=0·12). INTERPRETATION: We found no significant difference in estimated effectiveness of the two oral vaccines, supporting the recommendation that the more genetically stable nOPV2 should be preferred in cVDPV2 outbreak response. Our findings highlight the role of IPV and the necessity of strengthening routine immunisation, the primary route through which IPV is delivered. FUNDING: Bill & Melinda Gates Foundation and UK Medical Research Council.

The class IId bacteriocin thuricin-17 increases plant growth.

The mechanisms by which many plant growth promoting rhizobacteria (PGPR) affect plants are unknown. We recently isolated a rhizosphere bacterium (Bacillus thuringiensis NEB17), that promotes soybean growth and screened the liquid growth medium in which it grew for plant growth stimulating materials. We have also shown that it produces a bacteriocin (named by us as thuricin-17 and a member of the recently described class IId bacteriocins). Here we show that application of this bacteriocin to leaves (spray) or roots (drench) directly stimulates the growth of both a C(3) dicot (soybean) and a C(4) monocot (corn). This growth stimulation is similar in nature to that previously seen when plants are treated with Nod factors. Strain NEB17 contains three copies of the gene for thuricin 17 that code for identical amino acid sequences. These two lines of evidence suggest that the dual functions of these proteins may have constrained their evolution. This is the first report of direct plant growth enhancement by a bacteriocin.

Proteomic analysis of the bacteriocin thuricin 17 produced by Bacillus thuringiensis NEB17.

Thuricin 17 is a recently discovered bacteriocin produced by Bacillus thuringiensis NEB17. The objective of this work was to conduct a proteomic analysis of this bacteriocin. The partial N- and C-terminal amino-acid sequences of thuricin 17 have now been determined using the Edman degradation and matrix-assisted laser desorption ionization-quadrapole time of flight mass spectrometry (MS)/MS. A hydrophobic cluster analysis indicates that thuricin 17 contains a hydrophobic region, potentially corresponding to a membrane associated domain. Based on time of production, this bacteriocin may be produced as a secondary metabolite. Interestingly, thuricin 17 shares the same N-terminal sequence, DWTXWSXL, with a previously reported bacteriocin, Bacthuricin F4, produced by B. thuringiensis ssp. kurstaki strain BUPM4. This is the first time two bacteriocins from different Bacillus species have been shown to share similar N-terminal sequences.

Utility values for specific chronic myeloid leukemia chronic phase health states from the general public in the United Kingdom.

This study elicited time trade-off (TTO) and standard gamble (SG) preference values associated with four health states corresponding to response levels in chronic phase chronic myeloid leukemia (CML) from members of the general public in the UK (n = 235). Health states studied were treatment-free remission (TFR), complete molecular response (CMR, i.e. undetectable disease on treatment), molecular response and reappearance of detectable disease (i.e. relapse from TFR to molecular response requiring treatment). TFR was the most preferred health state (mean utility of 0.97 [TTO] and 0.87 [SG]) followed by CMR (mean utility of 0.96 [TTO] and 0.85 [SG]) followed by molecular response (mean utility of 0.94 [TTO] and 0.80 [SG]) followed by reappearance of detectable disease (mean utility of 0.90 [TTO] and 0.72 [SG]). SG values were significantly lower than TTO values (p < 0.001). The study demonstrated that different treatment responses may impact on the health-related quality of life of patients with chronic phase CML.

Utility values for chronic myelogenous leukemia chronic phase health states from the general public in the United Kingdom.

This study estimated time trade-off preference values associated with the four chronic myelogenous leukemia (CML) chronic phase-related health states (i.e. untreated, hematologic response, cytogenetic response and molecular response) among members of the general public in the UK (n = 241). All four health states were associated with decreases in preference values from full health. The molecular response to treatment was the most preferred health state (mean utility of 0.94). The second-most preferred health state was cytogenetic response followed by hematologic response (mean utilities were 0.89 and 0.80, respectively). The least preferred health state was untreated chronic phase CML (mean utility of 0.72). The utility values for each state were significantly different from one another (p < 0.001). This study demonstrated and quantified the impact that more robust treatment responses have on the health-related quality of life of patients with chronic phase CML.