Search results

Dosing interval is a major factor determining the quality of T cells induced by SARS-CoV-2 mRNA and adenoviral vector vaccines.

Functional T cell responses are crucial for protective immunity induced by COVID-19 vaccination, but factors influencing the quality of these responses are incompletely understood. We used an activation-induced marker (AIM) assay and single-cell transcriptomic sequencing to analyze SARS-CoV-2 spike-responsive T cells after mild SARS-CoV-2 infection or after one or two doses of mRNA-lipid nanoparticle (mRNA-LNP) or adenoviral-vectored COVID-19 vaccines. Our findings revealed broad functional and clonal heterogeneity in T cells generated by vaccination or infection, including multiple distinct effector populations. T cell function was largely conserved between COVID-19 vaccine platforms but was distinct compared with SARS-CoV-2 infection. Notably, the dosing interval greatly influenced the quality of T cells after two vaccine doses, particularly after mRNA-LNP vaccination, where a longer interval led to reduced inflammatory signaling and increased secondary proliferation. These insights enhance our understanding of SARS-CoV-2-specific T cells and inform the optimization of mRNA vaccination regimens.

MAIT and other innate-like T cells integrate adaptive immune responses to modulate interval-dependent reactogenicity to mRNA vaccines.

Adenoviral (Ad) vectors and mRNA vaccines exhibit distinct patterns of immune responses and reactogenicity, but underpinning mechanisms remain unclear. We longitudinally compared homologous ChAdOx1 nCoV-19 and BNT162b2 vaccination, focusing on cytokine-responsive innate-like lymphocytes-mucosal-associated invariant T (MAIT) cells and Vδ2+ γδ T cells-which sense and tune innate-adaptive cross-talk. Ad priming elicited robust type I interferon (IFN)-mediated innate-like T cell activation, augmenting T cell responses (innate-to-adaptive signaling), which was dampened at boost by antivector immunity. Conversely, mRNA boosting enhanced innate-like responses, driven by prime-induced spike-specific memory T cell-derived IFN-γ (adaptive-to-innate signaling). Extending the dosing interval dampened inflammation at boost because of waning T cell memory. In a separate vaccine trial, preboost spike-specific T cells predicted severe mRNA reactogenicity regardless of the priming platform or interval. Overall, bidirectional innate-like and adaptive cross-talk, and IFN-γ-licensed innate-like T cells, orchestrate interval-dependent early vaccine responses, suggesting modifiable targets for safer, more effective regimens.

Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine in children aged 6-17 years: Final results of a phase 2, single-blind, randomised controlled trial (COV006).

BACKGROUND: Paediatric COVID-19 vaccination programmes were initiated in response to the coronavirus pandemic declared by the World Health Organisation (WHO) in 2020. Ten COVID-19 vaccines received WHO Emergency Use Listing, however, only five were approved for use in children. ChAdOx1 nCoV-19 (AZD1222) was approved in adults in a two-dose regimen. We previously reported interim findings of a phase 2 study of ChAdOx1 nCoV-19 in children with immunogenicity, comparable with adults. Final results after 12 month follow-up are reported. METHODS: Single-blind, randomised controlled trial across four UK centres, recruiting 261 children and adolescents (aged 6-17 years). Participants received either two doses of ChAdOx1 nCoV-19 or Bexsero vaccine (controls). The primary outcome was safety (adverse events for 28 days following vaccination and serious adverse events throughout), and secondary outcome was immunogenicity (measured by SARS-CoV-2 anti-spike enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunosorbent spot (ELISpot)). FINDINGS: Five serious adverse events and four adverse events of special interest were reported. None were related to study vaccinations, and there were no deaths. Geometric mean titres (GMTs) from an anti-spike (Wuhan) ELISA in participants aged 6-11 years were 1 EU/ml (95% CI 1-2) at baseline versus 796 EU (95% CI 161-3948, n =4) at D364. In participants aged 12-17 years, GMTs were 1 EU/ml (95% CI 1-2, n=3) at baseline versus 1432 EU/ml (95% CI 2337-6083; n=6) at D364 (2 dose regimen at 112-day interval), compared to 3 EU/ml (95% CI 0-62) at baseline versus 392 EU/ml (95% CI 24, 6493; n=3) at D364 (2 dose regimen at a 28-day interval). INTERPRETATION: A two-dose regimen of ChAdOx1 nCoV-19 was immunogenic and safe in the trial population. No vaccine-related serious adverse events were reported. Immune responses persisted to 12 months in participants who did not experience breakthrough infection, This trial was registered with ISRCTN, trial number 15638344. FUNDING: The study was funded by the Department of Health and Social Care, through the National Institute for Health Research, and AstraZeneca.

WHO pandemic agreement.

Novel and optimized diagnostics for pediatric TB in endemic countries: NOD-pedFEND study protocol.

BACKGROUND: Pediatric tuberculosis is a major global public health challenge, with reliable diagnosis being a main obstacle to identifying and treating affected children. New and improved diagnostics, ideally on non-sputum samples, are urgently required, especially in the most vulnerable group of children under five years of age. Studies to date have been limited by small sample sizes and few bacteriologically-confirmed cases. Here, we describe the study protocol of the NIH-funded NOD-pedFEND study, which will be one of the largest diagnostic studies to date of children at greatest risk of tuberculosis. METHODS: In this prospective observational cohort study, we aim to evaluate existing and novel diagnostic assays, including pathogen- and host-based tests and combinations of tests. A consecutive cohort of children under five years of age with signs and symptoms of tuberculosis is enrolled in Uganda and Peru. All children undergo an extensive baseline workup with signs- and symptoms recording, microbiological reference tests, chest X-ray and tuberculin skin test for rigorous classification according to internationally recognized microbiological, composite reference and strict standards. An array of samples is collected for investigational tests. Follow-up visits are conducted at 2 weeks, 2 months and 6 months. A small cohort of healthy controls is enrolled to evaluate the specificity of selected diagnostics. The study has been approved by the relevant institutional review boards. DISCUSSION: With this large cohort study of children under five years of age, we aim to make an important contribution to the evaluation of new diagnostics for pediatric tuberculosis. By establishing a comprehensive biorepository, the study will also enable the assessment of novel tests as they become available during and after the study.

Heterologous COVID-19 vaccine schedule with protein-based prime (NVX-CoV2373) and mRNA boost (BNT162b2) induces strong humoral responses: results from COV-BOOST trial.

BACKGROUND: Heterologous schedules of booster vaccines for COVID-19 following initial doses of mRNA or adenoviral vector vaccines have been shown to be safe and immunogenic. There are few data on booster doses following initial doses of protein nanoparticle vaccines. METHODS: Participants of the phase 3 clinical trial of the COVID-19 vaccine NVX-CoV2373 (EudraCT 2020-004123-16) enrolled between September 28 and November 28, 2020, who received 2 doses of NVX-CoV2373 administered 21 days apart were invited to receive a third dose booster vaccine of BNT162b2 (wild type mRNA vaccine) as a sub-study of the COV-BOOST clinical trial, and were followed up for assessment of safety, reactogenicity and immunogenicity to day 242 post-booster. RESULTS: The BNT162b2 booster following two doses of NVX-COV2373 was well-tolerated. Most adverse events were mild to moderate, with no serious vaccine-related adverse events reported. Immunogenicity analysis showed a significant increase in spike IgG titres and T-cell responses post-third dose booster. Specifically, IgG levels peaked at day 14 with a geometric mean concentration (GMC) of 216,255 ELISA laboratory units (ELU)/mL (95% CI 191,083-244,743). The geometric mean fold increase from baseline to day 28 post-boost was 168.6 (95% CI 117.5-241.8). Spike IgG titres were sustained above baseline levels at day 242 with a GMC of 58,686 ELU/mL (95% CI 48,954-74,652), with significant decay between days 28 and 84 (geometric mean ratio 0.58, 95% CI 0.53-0.63). T-cell responses also demonstrated enhancement post-booster, with a geometric mean fold increase of 5.1 (95% CI 2.9-9.0) at day 14 in fresh samples and 3.0 (95% CI 1.8-4.9) in frozen samples as measured by ELISpot. In an exploratory analysis, participants who received BNT162b2 after two doses of NVX-COV2373 exhibited higher anti-spike IgG at Day 28 than those who received homologous three doses of BNT162b2, with a GMR of 5.02 (95% CI: 3.17-7.94). This trend remained consistent across all time points, indicating a similar decay rate between the two schedules. CONCLUSIONS: A BNT162b2 third dose booster dose in individuals primed with two doses of NVX-COV2373 is safe and induces strong and durable immunogenic responses, higher than seen in other comparable studies. These findings support the use and investigation of heterologous booster strategies and early investigation of heterologous vaccine technology schedules should be a priority in the development of vaccines against new pathogens.

Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 lineages circulating in Brazil.

Several COVID-19 vaccines have shown good efficacy in clinical trials, but there remains uncertainty about the efficacy of vaccines against different variants. Here, we investigate the efficacy of ChAdOx1 nCoV-19 (AZD1222) against symptomatic COVID-19 in a post-hoc exploratory analysis of a Phase 3 randomised trial in Brazil (trial registration ISRCTN89951424). Nose and throat swabs were tested by PCR in symptomatic participants. Sequencing and genotyping of swabs were performed to determine the lineages of SARS-CoV-2 circulating during the study. Protection against any symptomatic COVID-19 caused by the Zeta (P.2) variant was assessed in 153 cases with vaccine efficacy (VE) of 69% (95% CI 55, 78). 49 cases of B.1.1.28 occurred and VE was 73% (46, 86). The Gamma (P.1) variant arose later in the trial and fewer cases (N = 18) were available for analysis. VE was 64% (-2, 87). ChAdOx1 nCoV-19 provided 95% protection (95% CI 61%, 99%) against hospitalisation due to COVID-19. In summary, we report that ChAdOx1 nCoV-19 protects against emerging variants in Brazil despite the presence of the spike protein mutation E484K.

Respiratory syncytial virus hospitalisation by chronological month of age and by birth month in infants

Understanding the distribution of respiratory syncytial virus (RSV) disease burden by more granular age bands in infants is necessary for optimising infant RSV immunisation strategies. Using a Bayesian model, we synthesised published data from a systematic literature review and unpublished data shared by international collaborators for estimating the distribution of infant RSV hospitalisations by month of age. Based on local RSV seasonality data, we further developed and validated a web-based prediction tool for estimating infant RSV hospitalisation distribution by birth month. Although RSV hospitalisation burden mostly peaked at the second month of life and was concentrated in infants under six months globally, substantial variations were noted in the age distribution of RSV hospitalisation among infants born in different months. Passive immunisation strategies should ideally be tailored to the local RSV disease burden distribution by age and birth month to maximise their per-dose effectiveness before a universal immunisation can be achieved.

Gonorrhoea vaccination strategies should take into account all at risk and the potential for severe sequelae in women.

Recent Advances in Vaccine Development for Flaviviruses and Alphaviruses

Long-term respiratory mucosal immune memory to SARS-CoV-2 after infection and vaccination

A vaccine emergency – when to overrule parental refusal of vaccination at birth for prevention of vertical transmission of hepatitis B virus?

Plasmodium falciparum Subtilisin-like Domain-Containing Protein (PfSDP), a Cross-Stage Antigen, Elicits Short-Lived Antibody Response Following Natural Infection with Plasmodium falciparum

With the increasing detection of artemisinin resistance to front-line antimalarials in Africa and notwithstanding the planned roll-out of RTS’S and R21 in Africa, the search for new vaccines with high efficacy remains an imperative. Towards this endeavour, we performed in silico screening to identify Plasmodium falciparum gametocyte stage genes that could be targets of protection or diagnosis. Through the analysis we identified a gene, Pf3D7_1105800, coding for a Plasmodium falciparum subtilisin-like domain-containing protein (PfSDP) and thus dubbed the gene Pfsdp. Genetic diversity assessment revealed the Pfsdp gene to be relatively conserved across continents with signs of directional selection. Using RT qPCR and Western blots, we observed that Pfsdp is expressed in all developmental stages of the parasite both at the transcript and protein level. Immunofluorescence assays found PfSDP protein co-localizing with PfMSP-1 and partially with Pfs48/45 at the asexual and sexual stages, respectively. Further, we demonstrated that anti-PfSDP peptide-specific antibodies inhibited erythrocyte invasion by 20–60% in a dose-dependent manner, suggesting that PfSDP protein might play a role in merozoite invasion. We also discovered that PfSDP protein is immunogenic in children from different endemic areas with antibody levels increasing from acute infection to day 7 post-treatment, followed by a gradual decay. The limited effect of antibodies on erythrocyte invasion could imply that it might be more involved in other processes in the development of the parasite.

WHO preferred product characteristics for bivalent Salmonella Typhi/Paratyphi A vaccine for comprehensive protection against enteric fever– key considerations and research gaps

Bivalent prefusion F vaccination in pregnancy and respiratory syncytial virus hospitalisation in infants in the UK: results of a multicentre, test-negative, case-control study.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infections (ALRI) in infants younger than 6 months globally. A maternal bivalent RSV prefusion F (RSVpreF) vaccine was introduced to the UK in late summer in 2024 (August 12 in Scotland and September 1 in England), with all pregnant women at 28 weeks or more of gestation eligible for vaccination. We aimed to understand RSVpreF vaccine effectiveness in a real-world setting. METHODS: We conducted a multicentre, test-negative, case-control study to analyse the vaccine effectiveness of maternal RSVpreF vaccination against the primary outcome of hospitalisation (ie, admission to hospital) for RSV-associated ALRI in infants. Patient and public involvement from a group of parents informed the study protocol design. Included patients were infants with ALRI born after Aug 12, 2024 (Scotland), and Sept 1, 2024 (England), and therefore had mothers eligible for maternal vaccination, who were admitted to 30 hospital sites across the UK from Sept 30, 2024, to Jan 20, 2025, and tested for RSV. Infants were followed up until hospital discharge or death as an inpatient. Primary vaccine effectiveness of maternal RSVpreF vaccination against RSV-associated hospitalisation was calculated with the use of a conditional logistic regression adjusted by site, calendar month of hospital attendance for the infant, age, preterm birth, and sex. FINDINGS: We included 537 mother-infant pairs, in whom there were 391 RSV-positive infant cases (median age 1·63 months [IQR 0·94-2·26]) and 146 RSV-negative infant controls (1·41 months [0·77-2·03]). Of 537 recruited infants, 297 (55%) were male and 240 (45%) were female. Ethnicity data were available for 533 mothers, of whom 434 (81%) self-identified as White. The mothers of 73 (19%) RSV-positive cases and 60 (41%) RSV-negative controls had received RSVpreF vaccine before delivery. The adjusted effectiveness of maternal RSVpreF vaccination for preventing infant hospitalisation was 58% (95% CI 28-75) for infants whose mothers were vaccinated at any time before delivery and 72% (48-85) for infants whose mothers were vaccinated more than 14 days before delivery (39 [11%] of 357 RSV-positive cases vs 43 [33%] of 129 RSV-negative controls). INTERPRETATION: In the real-world setting of the first season of vaccine implementation in England and Scotland, maternal RSVpreF vaccination was effective and equivalent to trial settings in reducing the risk of hospitalisation in infants with RSV-associated ALRI. FUNDING: National Institute for Health and Care Research, The Wellcome Trust, and Imperial College London.

Salmonella Typhi gut invasion drives hypoxic immune subsets associated with disease outcomes

Salmonella Typhi (S. Typhi), the causative agent of typhoid disease, remains a major public health concern. Owing to the human-restricted nature of S. Typhi, studies of typhoid pathogenesis in animal models are limited to a murine non-typhoidal pathogen. More recently, human challenge models have been conducted, providing insight into immune correlates of infection outcomes, which are still incompletely understood. Here, we performed an integrated single-cell analysis of immune responses from the human S. Typhi challenge model and mouse model of typhoid disease, to associate biological mechanism with human infection outcome. Most prominent, we revealed immune subsets with a hypoxia-related signature in the blood of individuals who developed disease in the human challenge model. This signature was also evident in the mouse model in activated macrophages infiltrating into the Peyer’s patches, but not during infection with a mutant strain impaired for gut invasion. We further identified hypoxia-related signature as a general immune correlate of disease outcome in other infection-and inflammatory-related diseases. Collectively, we identified a hypoxia-associated immune signature that correlates with disease outcomes in humans. Using a mouse model, we demonstrated that this signature is driven by bacterial invasion to the Peyer’s patches, implicating a causal role in the pathogenesis of typhoid fever.

Nipah virus vaccines evaluated in pigs as a 'One Health' approach to protect public health.

Nipah virus (NiV) causes a severe neurological disease in humans. The first NiV outbreak, in Malaysia, involved pig-to-human transmission, that resulted in significant economic losses to the local pig industry. Despite the risk NiV poses to pig-dense regions, no licensed vaccines exist. This study therefore assessed three NiV vaccine candidates in pigs: (1) adjuvanted soluble NiV (s)G protein, (2) adjuvanted pre-fusion stabilised NiV (mcs)F protein, and (3) adenoviral vectored NiV G (ChAdOx1 NiV G). NiV sG induced the strongest neutralising antibody response, NiV mcsF induced antibodies best able to neutralise cell-cell fusion, whereas ChAdOx1 NiV G elicited CD8+ T-cell responses. Despite differences in immunogenicity, prime-boost immunisation with all candidates conferred a high degree of protection against NiV infection. Follow-up studies demonstrated longevity of immune responses and broadly comparable immune responses in Bangladeshi pigs under field conditions. These studies provide a platform for developing a NiV vaccine for pigs.

Understanding the interaction of upper respiratory tract infection with respiratory syncytial virus and Streptococcus pneumoniae using a human challenge model: a multicenter, randomized controlled study protocol.

BACKGROUND: Streptococcus pneumoniae (pneumococcus) and respiratory syncytial virus (RSV) are major causes of respiratory infections globally. Viral and bacterial co-infections are commonly observed in respiratory infections and there is evidence that these pathogens interact synergistically to evade host responses and lead to more severe disease. Notably, RSV seasonal outbreaks are associated with increased hospitalization and a subsequent peak in invasive pneumococcal disease cases, particularly in pediatric populations. Here, we summarize a protocol for a controlled human infection model aiming to evaluate pathogen interaction dynamics and immune responses in a combined pneumococcus and RSV model. The primary objective is to determine whether primary RSV challenge increases the risk of secondary pneumococcal colonization. METHODS: This is an open-label, multi-center, randomized controlled human co-infection study, inclusive of a pilot phase. Individuals will be randomized to primary inoculation with either pneumococcus (serotype 6B) or RSV (subtype RSV-A) intra-nasally on day 0 followed by a reciprocal challenge on day 7. During pilot phase A up to 10 participants will be monitored in an in-patient facility for 7-10 days following RSV-A challenge. If there are no safety concerns, we will then progress to an outpatient phase where participants will self-isolate at home. Clinical samples to be taken from participants include nasal swabs and washes for pathogen detection; and nasal cells, nasal lining fluid, and blood samples to examine mucosal and systemic immune responses. DISCUSSION: This work will lead to important scientific knowledge on the interaction and dynamics between pneumococcus and RSV. This knowledge could help inform pneumococcal and RSV vaccination strategies, particularly for groups at risk of developing severe pneumococcal and RSV disease. TRIAL REGISTRATION: The study is registered on ISRCTN (The UKs Clinical Study Registry). DOI https://doi.org/10.1186/ISRCTN12036902.

Communicating public health information to a global audience: an evaluation of methods to overcome barriers using a community-focussed approach

Defining the genetic determinants of CD8+ T cell receptor repertoire in the context of immune checkpoint blockade.

The relationship between genetic variation and CD8+ T cell receptor (TCR) repertoire usage in patients receiving immune checkpoint blockade (ICB) therapy for cancer is unexplored. We have conducted a genome-wide and human leukocyte antigen (HLA)-focused analysis of CD8+ TCR repertoire to identify genetic determinants of variable gene (V-gene) and CDR3 K-nucleotide oligomer usage from samples taken before and after ICB (n = 250). We identify 11 cis and 10 trans V-gene associations, primarily to the MHC, that meet genome-wide significance. TCR clones containing HLA associated V-genes were less stable across treatment, while, at the single-cell level, genetically associated clones demonstrate subset enrichment and increased tumor reactivity expression profiles. Notably, patients with HLA-matched TCR clones demonstrate improved overall survival. Our work indicates a complex relationship between genotype and TCR repertoire in the context of ICB treatment, with implications for understanding factors relating to therapeutic response and patient outcomes.