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Bordetella pertussis epidemics persist as transmission remains unabated despite high acellular pertussis vaccination rates. BPZE1, a live attenuated intranasal pertussis vaccine, was designed to prevent B pertussis infection and disease. We aimed to assess the immunogenicity and safety of BPZE1 compared with the tetanus–diphtheria–acellular pertussis vaccine (Tdap). In this double-blind, phase 2b trial at three research centres in the USA, healthy adults aged 18–50 years were randomly assigned (2:2:1:1) via a permuted block randomisation schedule to receive BPZE1 vaccination followed by BPZE1 attenuated challenge, BPZE1 vaccination followed by placebo challenge, Tdap followed by BPZE1 attenuated challenge, or Tdap followed by placebo challenge. On day 1, lyophilised BPZE1 was reconstituted with sterile water and given intranasally (0·4 mL delivered to each nostril), whereas Tdap was given intramuscularly. To maintain masking, participants in the BPZE1 groups received an intramuscular saline injection, and those in the Tdap groups received intranasal lyophilised placebo buffer. The attenuated challenge took place on day 85. The primary immunogenicity endpoint was the proportion of participants achieving nasal secretory IgA seroconversion against at least one B pertussis antigen on day 29 or day 113. Reactogenicity was assessed up to 7 days after vaccination and challenge, and adverse events were recorded for 28 days after vaccination and challenge. Serious adverse events were monitored throughout the study. This trial is registered with ClinicalTrials.gov, NCT03942406. Between June 17 and Oct 3, 2019, 458 participants were screened and 280 were randomly assigned to the main cohort: 92 to the BPZE1–BPZE1 group, 92 to the BPZE1–placebo group, 46 to the Tdap–BPZE1 group, and 50 to the Tdap–placebo group. Seroconversion of at least one B pertussis-specific nasal secretory IgA was recorded in 79 (94% [95% CI 87–98]) of 84 participants in the BPZE1–BPZE1 group, 89 (95% [88–98]) of 94 in the BPZE1–placebo group, 38 (90% [77–97]) of 42 in the Tdap–BPZE1 group, and 42 (93% [82–99]) of 45 in the Tdap–placebo group. BPZE1 induced broad and consistent B pertussis-specific mucosal secretory IgA responses, whereas Tdap did not induce consistent mucosal secretory IgA responses. Both vaccines were well tolerated, with mild reactogenicity and no serious adverse events related to study vaccination. BPZE1 induced nasal mucosal immunity and produced functional serum responses. BPZE1 has the potential to avert B pertussis infections, which ultimately could lead to reduced transmission and diminished epidemic cycles. These results should be confirmed in large phase 3 trials. ILiAD Biotechnologies.

Pertussis, caused by , remains a global health problem, despite high vaccine coverage. In countries with high acellular pertussis vaccine (aPV) coverage, pertactin-negative strains emerged due to vaccine pressure on the sole bactericidal target of aPVs. In contrast, the live attenuated intranasal vaccine BPZE1 induces bactericidal antibodies to multiple antigenic targets that kill pertactin-positive and pertactin-negative strains. Here, we developed two high-throughput human complement-mediated serum bactericidal assays (SBA) using clinical samples to demonstrate bactericidal activity against . Assay accuracy, precision, linearity, range and robustness of the SBAs against pertactin-positive and pertactin-negative strain B1917 were determined using a panel of commercial and clinical trial samples. The assay was used to analyze a cohort of BPZE1 and tetanus-diphtheria-acellular pertussis (Tdap) vaccinee samples at baseline and 28 days post-vaccination from a phase 2b clinical trial. Inter- and intra-assay variability of both assays had coefficients of variation for repeatability < 20% and for intermediate precision of <30%. The assays measured titers ranging from ~8 to ~20,000 and showed high linearity (R > 0.98) between bactericidal titers and serum dilutions. On clinical samples, BPZE1 induced similar bactericidal activity as Tdap against pertactin-positive , despite inducing lower anti-aP antigen IgG concentrations than Tdap. Additionally, BPZE1 induced serum bactericidal activity against pertactin-negative , while Tdap did not. High-throughput SBAs were developed and qualified against pertactin-positive and pertactin-negative , enabling measurement of 120 samples per day per analyst. These assays will support clinical development of next-generation pertussis vaccines, including BPZE1.

Phenethyl isothiocyanate (PEITC) is a naturally occurring electrophile which depletes intracellular glutathione (GSH) levels and triggers accumulation of reactive oxygen species (ROS). PEITC is of considerable interest as a potential chemopreventive/chemotherapeutic agent, and in this work, we have investigated the effects of PEITC on human breast cancer cell lines. Whereas PEITC readily induced apoptosis in MDA-MB-231 cells (associated with rapid activation of caspases 9 and 3, and decreased expression of BAX), MCF7 cells were relatively resistant to the apoptosis promoting effects of PEITC. The relative resistance of MCF7 cells was associated with high basal expression of NRF2, a transcription factor that coordinates cellular protective responses to oxidants and electrophiles and raised intracellular levels of GSH. This raised basal expression of NRF2 appeared to be a response to on-going production of ROS, since treatment with the antioxidant and GSH precursor N-acetylcysteine (NAC) reduced NRF2 expression. Moreover, pre-treatment of MDA-MB-231 cells with NAC rendered these cells relatively resistant to PEITC-induced apoptosis. In summary, our data confirm that PEITC may be an effective chemopreventive/therapeutic agents for breast cancer. However, differences in the basal expression of NRF2 and resultant changes in GSH levels may be an important determinant of sensitivity to PEITC-induced apoptosis.

Whooping cough is a re-emerging respiratory tract infection. It has become clear that there is a need for better understanding of protective immune responses and variation between Bordetella pertussis strains to aid the development of improved vaccines. In order to survive in the host, B. pertussis has evolved mechanisms to evade complement-mediated killing, including the ability to bind complement-regulatory proteins. Here we evaluate the variation in interactions with the complement system among recently isolated strains. Isolates whose genomes appear highly similar and cluster together on a SNP-based dendrogram were found to vary significantly in resistance to complement-mediated killing and in the deposition of C3b/iC3b, C5b-9 and C1 esterase inhibitor (C1-INH). The key role of Vag8 as a receptor for C1-INH was confirmed and its expression was shown to vary in a panel of isolates. A Vag8 knockout mutant showed increased sensitivity to complement-mediated killing. Antibodies in convalescent sera blocked C1-INH binding to B. pertussis and may play an important role in natural immunity.

Dietary intake of isothiocyanates (ITC) has been associated with reduced cancer risk. The dietary phenethyl ITC (PEITC) has previously been shown to decrease the phosphorylation of the translation regulator 4E binding protein 1 (4E-BP1). Decreased 4E-BP1 phosphorylation has been linked to the inhibition of cancer cell survival and decreased activity of the transcription factor hypoxia-inducible factor (HIF), a key positive regulator of angiogenesis, and may therefore contribute to potential anti-cancer effects of PEITC. In the present study, we have investigated the in vitro and in vivo effects of watercress, which is a rich source of PEITC. We first demonstrated that, similar to PEITC, crude watercress extracts inhibited cancer cell growth and HIF activity in vitro. To examine the effects of dietary intake of watercress, we obtained plasma and peripheral blood mononuclear cells following the ingestion of an 80 g portion of watercress from healthy participants who had previously been treated for breast cancer. Analysis of PEITC in plasma samples from nine participants demonstrated a mean maximum plasma concentration of 297 nm following the ingestion of watercress. Flow cytometric analysis of 4E-BP1 phosphorylation in peripheral blood cells from four participants demonstrated significantly reduced 4E-BP1 phosphorylation at 6 and 8 h following the ingestion of watercress. Although further investigations with larger numbers of participants are required to confirm these findings, this pilot study suggests that flow cytometry may be a suitable approach to measure changes in 4E-BP1 phosphorylation following the ingestion of watercress, and that dietary intake of watercress may be sufficient to modulate this potential anti-cancer pathway.

A novel coronavirus, SARS-CoV-2, has been identified as the causative agent of the current COVID-19 pandemic. Animal models, and in particular non-human primates, are essential to understand the pathogenesis of emerging diseases and to assess the safety and efficacy of novel vaccines and therapeutics. Here, we show that SARS-CoV-2 replicates in the upper and lower respiratory tract and causes pulmonary lesions in both rhesus and cynomolgus macaques. Immune responses against SARS-CoV-2 are also similar in both species and equivalent to those reported in milder infections and convalescent human patients. This finding is reiterated by our transcriptional analysis of respiratory samples revealing the global response to infection. We describe a new method for lung histopathology scoring that will provide a metric to enable clearer decision making for this key endpoint. In contrast to prior publications, in which rhesus are accepted to be the preferred study species, we provide convincing evidence that both macaque species authentically represent mild to moderate forms of COVID-19 observed in the majority of the human population and both species should be used to evaluate the safety and efficacy of interventions against SARS-CoV-2. Importantly, accessing cynomolgus macaques will greatly alleviate the pressures on current rhesus stocks. Non-human primates are important animal models for studying SARS-CoV-2 infection. Here, Salguero et al. directly compare rhesus and cynomolgus macaques and show that both species represent COVID-19 disease of mild clinical cases, and provide a lung histopathology scoring system.

There is a vital need for authentic COVID-19 animal models to enable the pre-clinical evaluation of candidate vaccines and therapeutics. Here we report a dose titration study of SARS-CoV-2 in the ferret model. After a high (5 × 10 6  pfu) and medium (5 × 10 4  pfu) dose of virus is delivered, intranasally, viral RNA shedding in the upper respiratory tract (URT) is observed in 6/6 animals, however, only 1/6 ferrets show similar signs after low dose (5 × 10 2  pfu) challenge. Following sequential culls pathological signs of mild multifocal bronchopneumonia in approximately 5–15% of the lung is seen on day 3, in high and medium dosed groups. Ferrets re-challenged, after virus shedding ceased, are fully protected from acute lung pathology. The endpoints of URT viral RNA replication & distinct lung pathology are observed most consistently in the high dose group. This ferret model of SARS-CoV-2 infection presents a mild clinical disease. SARS-CoV-2 induces mild infection in ferret model. Here, Ryan et al. characterise optimal infection dosage inducing upper respiratory tract (UTR) viral shedding, progression time of viral shedding, and pathology in ferrets and finally provide evidence for protection after re-challenge.

Vaccinating women against pertussis in pregnancy protects young infants from severe disease and death. Vaccination-induced maternally derived antibodies, however, might subsequently modulate (and specifically blunt) the infant's serological response to their primary series of pertussis vaccinations. We examined the effect of pertussis immunisation in pregnancy on the immunogenicity of primary acellular or whole-cell pertussis vaccines in a west African cohort. GaPs was a randomised, controlled, double-blind, phase 4 trial conducted in The Gambia. We used a predefined block randomisation scheme to randomly assign healthy, HIV-negative, pregnant participants (1:1) to receive a pertussis-containing (tetanus-diphtheria-acellular pertussis-inactivated polio virus [Tdap-IPV]) or tetanus-toxoid only vaccine at 28–34 weeks' gestation. At the same time, their infants were randomly assigned (1:1) to receive diphtheria-tetanus-acellular pertussis (DTaP) or diphtheria-tetanus-whole-cell pertussis (DTwP) primary vaccine at 8, 12, and 16 weeks postnatally. Participants and trial staff were masked to the allocation of the maternal vaccine. The field team and participants became unmasked to the allocation of the infant vaccine at 16 weeks; laboratory staff and all other investigators remained masked to infant vaccine allocation until the end of the trial. The primary outcome was geometric mean concentration (GMC) of infant pertussis toxin-specific antibodies at 20 weeks and 9 months postnatally and was assessed in infants who received all three doses of the primary vaccine. Secondary outcomes included memory B-cell responses, and exploratory outcomes were total pertussis-specific antibody binding concentrations and functional antibody titres (pertussis toxin-specific neutralising activity [PTNA] and serum bactericidal activity [SBA]). Vaccine reactogenicity was assessed in mothers and infants for 3 days after each vaccine dose. Pregnant women had an extra safety visit 7 days after vaccination. The study is registered with ClinicalTrials.gov, NCT03606096. Between Feb 13, 2019, and May 17, 2021, we enrolled 343 maternal–infant pairs. 239 (77%) infants were included in the per-protocol immunogenicity analysis. Among infants of mothers receiving Tdap-IPV in pregnancy, at 20 weeks postnatally, the GMCs of anti-pertussis toxin IgG were more than three-fold lower in infants vaccinated with three doses of DTwP (n=64) than in infants vaccinated with three doses of DTaP (n=53; adjusted geometric mean ratio 0·28, 98·75% CI 0·16–0·50). This difference persisted up to 9 months (0·31, 0·17–0·55). Conversely, among infants born to tetanus toxoid-immunised mothers, post-vaccination GMCs of anti-pertussis toxin IgG at 9 months were higher in those vaccinated with DTwP (n=58) than in those vaccinated with DTaP (n=64; 2·02, 1·15–3·55). Tdap-IPV immunisation in pregnancy blunted anti-pertussis toxin IgG following primary vaccination in all infants but particularly in those receiving DTwP, with GMCs of anti-pertussis toxin IgG more than eight-fold lower in DTwP-vaccinated infants born to Tdap-IPV-vaccinated mothers than in DTwP-vaccinated infants born to tetanus toxoid-immunised mothers (0·12, 98·75% CI 0·07–0·22 at 20 weeks; 0·07, 0·03–0·17 at 9 months). Similarly, DTwP-vaccinated infants born to Tdap-IPV-vaccinated mothers also showed significant blunting of PTNA, SBA, total pertussis-specific antibody binding, and memory B-cell responses after primary immunisation, whereas minimal blunting was observed among DTaP-vaccinated infants. However, the absolute levels of these responses generated by DTwP-vaccinated infants remained similar to or, in many cases, were higher than those generated by DTaP-vaccinated infants. There was no difference in reactogenicity between the two maternal vaccines, with most reactions graded 0 or 1. There were no serious adverse events related to vaccination or trial participation. Vaccinating women with Tdap-IPV in pregnancy was safe and well tolerated in a sub-Saharan African setting and boosted the quantity and quality of pertussis-specific antibodies in infants in early life. Although Tdap-IPV was associated with relative blunting of the immune response to the DTwP primary vaccination series, pertussis-specific antibody quality and memory B-cell responses were nevertheless preserved, regardless of the vaccine given during pregnancy. GaPs was conducted as part of the Pertussis Correlates Of Protection Europe (PERISCOPE) consortium, which received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement 115910. This Joint Undertaking receives support from the EU's Horizon 2020 research and innovation programme, the European Federation of Pharmaceutical Industries and Associations, and the Bill & Melinda Gates Foundation.

The trajectories of acquired immunity to severe acute respiratory syndrome coronavirus 2 infection are not fully understood. We present a detailed longitudinal cohort study of UK healthcare workers prior to vaccination, presenting April-June 2020 with asymptomatic or symptomatic infection. Here we show a highly variable range of responses, some of which (T cell interferon-gamma ELISpot, N-specific antibody) wane over time, while others (spike-specific antibody, B cell memory ELISpot) are stable. We use integrative analysis and a machine-learning approach (SIMON - Sequential Iterative Modeling OverNight) to explore this heterogeneity. We identify a subgroup of participants with higher antibody responses and interferon-gamma ELISpot T cell responses, and a robust trajectory for longer term immunity associates with higher levels of neutralising antibodies against the infecting (Victoria) strain and also against variants B.1.1.7 (alpha) and B.1.351 (beta). These variable trajectories following early priming may define subsequent protection from severe disease from novel variants. The engagement of immunological memory is a key component to the protective anti-SARS-CoV-2 B and T cell responses. Here the authors assess the B and T cells of a cohort of UK healthcare workers in response to infection and longitudinally track the compartment showing distinct trajectories following early priming.

The mutation profile of the SARS-CoV-2 Omicron (lineage BA.1) variant posed a concern for naturally acquired and vaccine-induced immunity. We investigated the ability of prior infection with an early SARS-CoV-2 ancestral isolate (Australia/VIC01/2020, VIC01) to protect against disease caused by BA.1. We established that BA.1 infection in naïve Syrian hamsters resulted in a less severe disease than a comparable dose of the ancestral virus, with fewer clinical signs including less weight loss. We present data to show that these clinical observations were almost absent in convalescent hamsters challenged with the same dose of BA.1 50 days after an initial infection with ancestral virus. These data provide evidence that convalescent immunity against ancestral SARS-CoV-2 is protective against BA.1 in the Syrian hamster model of infection. Comparison with published pre-clinical and clinical data supports consistency of the model and its predictive value for the outcome in humans. Further, the ability to detect protection against the less severe disease caused by BA.1 demonstrates continued value of the Syrian hamster model for evaluation of BA.1-specific countermeasures.