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As COVID-19 spreads through the world, most cases to date are in middle- and high-income nations. The impact on resource-poor nations remains unknown. Amongst many factors likely to affect the impact of COVID-19 in these areas, co-infections need to be considered. Here, we discuss whether the immunomodulatory effects of helminth infections may affect COVID-19 severity.Helminth co-infections can skew systemic immunity towards type 2 responses. Here, Bradbury and colleagues consider how this may impact the severity of COVID-19 in helminth-endemic regions.

Neurocysticercosis (NCC) is caused by infection of the brain by larvae of the parasitic cestode Taenia solium . It is the most prevalent parasitic infection of the central nervous system and one of the leading causes of adult-acquired epilepsy worldwide. However, little is known about how cestode larvae affect neurons directly. To address this, we used whole-cell patch-clamp electrophysiology and calcium imaging in rodent and human brain slices to identify direct effects of cestode larval products on neuronal activity. We found that both whole cyst homogenate and excretory/secretory products of cestode larvae have an acute excitatory effect on neurons, which can trigger seizure-like events in vitro . This effect was mediated by glutamate receptor activation but not by nicotinic acetylcholine receptors, acid-sensing ion channels, or Substance P. Glutamate-sensing fluorescent reporters (iGluSnFR) and amino acid assays revealed that the larval homogenate of the cestodes Taenia crassiceps and Taenia solium contained high concentrations of the amino acids glutamate and aspartate. Furthermore, we found that larvae of both species consistently produce and release these excitatory amino acids into their immediate environment. Our findings suggest that perturbations in glutamatergic signalling may play a role in seizure generation in NCC. One of the main causes of epilepsy in adults – particularly in developing countries – is a parasitic brain infection called neurocysticercosis. This can happen when people swallow tapeworm eggs, which hatch into larvae and migrate throughout the body. When these larvae infect the brain, they form structures called cysts, which can cause seizures. It is thought that inflammation in the brain contributes to the development of seizures in neurocysticercosis, but how this might work is still poorly understood. The larvae produce chemicals that can interact with nearby cells in the body, including the defensive cells of our immune system. However, it remains unknown whether those chemicals also interact with brain cells. De Lange, Tomes et al. set out to determine if tapeworm larvae produced any specific chemicals that affect the activity of brain cells, and if they might play a role in epileptic seizures. To do this, the researchers collected materials from tapeworm larvae, which included both the substances they naturally released and a mixture made from crushed whole larvae. They then applied these substances to brain tissue grown in cell culture while recording the electrical activity of individual brain cells. Experiments using brain tissue derived from rats, mice and humans revealed that the larval products made brain cells more excited and led to them firing more electrical signals than normal. This excitation was strong enough to trigger larger patterns of activity across the brain tissue that mimicked the effect of an epileptic seizure. Further biochemical analysis of the larval products and the larvae themselves revealed that tapeworm larvae continuously release a chemical called glutamate, which is known to excite brain cells. These results suggested that tapeworm larvae might cause epilepsy by producing excess glutamate and overexciting brain cells – a mechanism similar to the way that other brain conditions, like tumors, also trigger seizures. This work has revealed a new mechanism for how tapeworm larvae might cause seizures in neurocysticercosis. The next step will be understanding how the larvae release glutamate into the brain, for example, if they actively produce it, or if it is passively released when they die. In the future, de Lange et al. hope this knowledge will help develop new treatments that help prevent seizures in people with neurocysticercosis.

The filoviruses, marburgvirus and ebolavirus, cause epidemics of haemorrhagic fever with high casefatality rates. The severe illness results from a complex of pathogenetic mechanisms that enable the virus to suppress innate and adaptive immune responses, infect and kill a broad variety of cell types, and elicit strong inflammatory responses and disseminated intravascular coagulation, producing a syndrome resembling septic shock. Most experimental data have been obtained on Zaire ebolavirus, which causes uniformly lethal disease in experimentally infected non-human primates but produces a broader range of outcomes in naturally infected human beings. 10–30% of patients can survive the illness by mobilising adaptive immune responses, and there is limited evidence that mild or symptomless infections also occur. The other filoviruses that have caused human disease, Sudan ebolavirus, Ivory Coast ebolavirus, and marburgvirus, produce a similar illness but with somewhat lower case-fatality rates. Variations in outcome during an epidemic might be due partly to genetically determined differences in innate immune responses to the viruses. Recent studies in non-human primates have shown that blocking of certain host responses, such as the coagulation cascade, can result in reduced viral replication and improved host survival.

Vaccination against COVID-19 has been pivotal in reducing the global burden of the disease. However, Phase III trial results and observational studies underscore differences in efficacy across vaccine technologies and dosing regimens. Notably, mRNA vaccines have exhibited superior effectiveness compared to Adenovirus (AdV) vaccines, especially with extended dosing intervals. Using in-host mechanistic modelling, this study elucidates these variations and unravels the biological mechanisms shaping the immune responses at the cellular level. We used data on the change in memory B cells, plasmablasts, and antibody titres after the second dose of a COVID-19 vaccine for Australian healthcare workers. Alongside this dataset, we constructed a kinetic model of humoral immunity which jointly captured the dynamics of multiple immune markers, and integrated hierarchical effects into this kinetics model, including age, dosing schedule, and vaccine type. Our analysis estimated that mRNA vaccines induced 2.1 times higher memory B cell proliferation than AdV vaccines after adjusting for age, interval between doses and priming dose. Additionally, extending the duration between the second vaccine dose and priming dose beyond 28 days boosted neutralising antibody production per plasmablast concentration by 30%. We also found that antibody responses after the second dose were more persistent when mRNA vaccines were used over AdV vaccines and for longer dosing regimens. Reconstructing in-host kinetics in response to vaccination could help optimise vaccine dosing regimens, improve vaccine efficacy in different population groups, and inform the design of future vaccines for enhanced protection against emerging pathogens.

Background The diagnosis of strongyloidiasis is challenging. Serological tests are acknowledged to have high sensitivity, but issues due to cross-reactions with other parasites, native parasite antigen supply and intrinsic test variability do occur. Assays based on recombinant antigens could represent an improvement. The aim of this study was to assess the sensitivity and specificity of two novel immunoglobulin (Ig)G and IgG4 enzyme-linked immunosorbent assays (ELISAs) based on the recombinant antigens NIE/SsIR for the diagnosis of strongyloidiasis. Methods This was a retrospective diagnostic accuracy study. We included serum samples collected from immigrants from strongyloidiasis endemic areas for whom there was a matched result for Strongyloides stercoralis on agar plate culture and/or PCR assay, or a positive microscopy for S. stercoralis larvae. For the included samples, results were also available from an in-house indirect fluorescent antibody test (IFAT) and a commercial (Bordier ELISA; Bordier Affinity Products SA) ELISA. We excluded: (i) samples with insufficient serum volume; (ii) samples from patients treated with ivermectin in the previous 6 months; and (iii) sera from patients for whom only routine coproparasitology was performed after formol–ether concentration, if negative for S. stercoralis larvae. The performance of the novel assays was assessed against: (i) a primary reference standard, with samples classified as negative/positive on the basis of the results of fecal tests; (ii) a composite reference standard (CRS), which also considered patients to be positive who had concordant positive results for the IFAT and Bordier ELISA or with a single “high titer” positive result for the IFAT or Bordier ELISA. Samples with a single positive test, either for the IFAT or Bordier ELISA, at low titer, were considered to be “indeterminate,” and analyses were carried out with and without their inclusion. Results When assessed against the primary reference standard, the sensitivities of the IgG and IgG4 ELISAs were 92% (95% confidence interval [CI]: 88–97%) and 81% (95% CI: 74–87%), respectively, and the specificities were 91% (95% CI: 88–95%) and 94% (95% CI: 91–97%), respectively. When tested against the CRS, the IgG ELISA performed best, with 78% sensitivity (95% CI: 72–83%) and 98% specificity (95% CI: 96–100%), when a cut-off of 0.675 was applied and the indeterminate samples were excluded from the analysis. Conclusion The NIE-SsIR IgG ELISA demonstrated better accuracy than the IgG4 assay and was deemed promising particularly for serosurveys in endemic areas. Graphical abstract

Studies on binding and neutralizing antibody responses to COVID-19 vaccines and breakthrough infections were frequently confounded by unsuspected exposure to intercurrent natural infections with SARS-CoV-2 in the community particularly during year 1 and 2 of the pandemic. This study is extraordinary in that it was conducted in Australia, where SARS-CoV-2 circulation was largely contained by public health and social measures for the first 2 years of the pandemic. We followed well-defined study populations who received vaccines in a natural infection-free setting or a separate subgroup who had natural infection. Thus, the study provides unique insights in infection-naïve, vaccinated individuals and those with breakthrough infections with Omicron variants. In this setting, we had an opportunity to demonstrate evidence of antigenic imprinting, with neutralizing antibody responses to the ancestral vaccine antigen being higher than responses to the infecting Omicron variant.

Antigen tests for diagnosis and disease monitoring in some types of neurocysticercosis (NCC) are useful but access to testing has been limited by availability of proprietary reagents and/or kits. Three previously identified IgM-secreting hybridomas whose IgM products demonstrated specificity to Taenia solium underwent variable heavy and light chain sequencing and isotype conversion to mouse IgG. Screening of these recombinantly expressed IgG anti-Ts hybridomas, identified one (TsG10) with the highest affinity to crude Taenia antigen. TsG10 was then used as a capture antibody in a sandwich antigen detection immunoassay in combination with either a high titer polyclonal anti-Ts antibody or with biotinylated TsG10 (termed TsG10*bt). Using serum, plasma, and CSF samples from patients with active NCC and those from NCC-uninfected patients, ROC curve analyses demonstrated that the TsG10-TsG10-*bt assay achieved a 98% sensitivity and 100% specificity in detecting samples known to be antigen positive and outperformed the polyclonal based assay (sensitivity of 93% with 100% specificity). By comparing levels of Ts antigen (Ag) in paired CSF (n = 10) or plasma/serum (n = 19) samples from well-characterized patients with extra-parenchymal NCC early in infection and at the time of definitive cure, all but 2 (1 from CSF and 1 from plasma) became undetectable. There was a high degree of correlation (r = 0.98) between the Ag levels detected by this new assay and levels found by a commercial assay. Pilot studies indicate that this antigen can be detected in the urine of patients with active NCC. A newly developed recombinant monoclonal antibody-based Ts Ag detection immunoassay is extremely sensitive in the detection of extra-parenchymal NCC and can be used to monitor the success of treatment in the CSF, serum/plasma and urine. The ability to produce recombinant TsG10 at scale should enable use of this antigen detection immunoassay wherever NCC is endemic. ClinicalTrials.gov Identifiers: NCT00001205 - & NCT00001645.

Pfs25 and Pvs25, surface proteins of mosquito stage of the malaria parasites P. falciparum and P. vivax, respectively, are leading candidates for vaccines preventing malaria transmission by mosquitoes. This single blinded, dose escalating, controlled Phase 1 study assessed the safety and immunogenicity of recombinant Pfs25 and Pvs25 formulated with Montanide ISA 51, a water-in-oil emulsion. The trial was conducted at The Johns Hopkins Center for Immunization Research, Washington DC, USA, between May 16, 2005-April 30, 2007. The trial was designed to enroll 72 healthy male and non-pregnant female volunteers into 1 group to receive adjuvant control and 6 groups to receive escalating doses of the vaccines. Due to unexpected reactogenicity, the vaccination was halted and only 36 volunteers were enrolled into 4 groups: 3 groups of 10 volunteers each were immunized with 5 microg of Pfs25/ISA 51, 5 microg of Pvs25/ISA 51, or 20 microg of Pvs25/ISA 51, respectively. A fourth group of 6 volunteers received adjuvant control (PBS/ISA 51). Frequent local reactogenicity was observed. Systemic adverse events included two cases of erythema nodosum considered to be probably related to the combination of the antigen and the adjuvant. Significant antibody responses were detected in volunteers who completed the lowest scheduled doses of Pfs25/ISA 51. Serum anti-Pfs25 levels correlated with transmission blocking activity. It is feasible to induce transmission blocking immunity in humans using the Pfs25/ISA 51 vaccine, but these vaccines are unexpectedly reactogenic for further development. This is the first report that the formulation is associated with systemic adverse events including erythema nodosum. ClinicalTrials.gov NCT00295581.

Mortality is a key statistic for public health globally, and mortality reduction is a key target of ‘End TB’ strategy. However, cause of death in relation to tuberculosis (TB) may be controversial, and we aimed to evaluate classification in Australia. We surveyed Australian clinicians and public health officers, presenting a variety of scenarios. Respondents were asked to classify each scenario with regards to whether TB was considered causative, contributory or not related to death. Fifty‐nine individuals completed the survey. Respondents were experienced TB clinicians and public health officers (median 14 years of TB care experience), with a majority having recently been involved in death certification/classification. In most scenarios, there was substantial variation, particularly where death was related to TB medications, or if an alternative contributing process was recognised, such as cardiovascular complications. Variation in classification was not evidently associated with classification experience. We found significant variation in cause of death classification among experienced TB clinicians and public health officers, using representative TB death scenarios. Consensus and transparency with regards to classification would assist in more uniform cause of death classification across jurisdictions and allow for better tracking of this critical performance measure.