Diagnosis of Multisystem Inflammatory Syndrome in Children by a Whole-Blood Transcriptional Signature.

BACKGROUND: To identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki disease (KD), bacterial infections, and viral infections. METHODS: Children presenting with MIS-C to participating hospitals in the United Kingdom and the European Union between April 2020 and April 2021 were prospectively recruited. Whole-blood RNA Sequencing was performed, contrasting the transcriptomes of children with MIS-C (n = 38) to those from children with KD (n = 136), definite bacterial (DB; n = 188) and viral infections (DV; n = 138). Genes significantly differentially expressed (SDE) between MIS-C and comparator groups were identified. Feature selection was used to identify genes that optimally distinguish MIS-C from other diseases, which were subsequently translated into RT-qPCR assays and evaluated in an independent validation set comprising MIS-C (n = 37), KD (n = 19), DB (n = 56), DV (n = 43), and COVID-19 (n = 39). RESULTS: In the discovery set, 5696 genes were SDE between MIS-C and combined comparator disease groups. Five genes were identified as potential MIS-C diagnostic biomarkers (HSPBAP1, VPS37C, TGFB1, MX2, and TRBV11-2), achieving an AUC of 96.8% (95% CI: 94.6%-98.9%) in the discovery set, and were translated into RT-qPCR assays. The RT-qPCR 5-gene signature achieved an AUC of 93.2% (95% CI: 88.3%-97.7%) in the independent validation set when distinguishing MIS-C from KD, DB, and DV. CONCLUSIONS: MIS-C can be distinguished from KD, DB, and DV groups using a 5-gene blood RNA expression signature. The small number of genes in the signature and good performance in both discovery and validation sets should enable the development of a diagnostic test for MIS-C.

The collective voice of early phase COVID-19 vaccine trial participants: Insights for improving confidence in novel vaccines.

In early 2020, adult volunteers were invited to participate in a first-in-human trial of the COVID-19 vaccine, ChAdOx1 nCoV-19, in the United Kingdom (UK) at the height of the global pandemic when there was uncertainty regarding vaccine efficacy and side-effects. We conducted a retrospective survey of these uniquely situated individuals to gain insight into their views about the risks, motivations, and expectations of the trial and potential vaccine deployment. Our data from 349 respondents show that these volunteers were educated to a high-level with a clear understanding of the seriousness of the COVID-19 pandemic, as well as an appreciation of the role of science and research in developing a vaccine to address this global problem. Individuals were primarily motivated with altruistic intent and expressed a desire to contribute to the scientific effort. Respondents appreciated that their participation was associated with risk but appeared comfortable that this risk was low. Through our analysis, we highlight these individuals as a group with strong levels of trust in science and a sense of societal responsibility, and therefore are a potential valuable resource to improve confidence in novel vaccines. Vaccine trial participants could offer a credible collective voice to support positive messaging around vaccination.

Evaluation of T cell responses to naturally processed variant SARS-CoV-2 spike antigens in individuals following infection or vaccination

Most existing studies characterising SARS-CoV-2-specific T cell responses are peptide based. This does not allow evaluation of whether tested peptides are processed and presented canonically. In this study, we use recombinant vaccinia virus (rVACV)-mediated expression of SARS-CoV-2 spike protein and SARS-CoV-2 infection of ACE-2-transduced B cell lines to evaluate overall T cell responses in a small cohort of recovered COVID-19 patients and uninfected donors vaccinated with ChAdOx1 nCoV-19. We show that rVACV expression of SARS-CoV-2 antigen can be used as an alternative to SARS-CoV-2 infection to evaluate T cell responses to naturally processed spike antigens. In addition, rVACV system can be used to evaluate the cross-reactivity of memory T cells to variants of concern (VOCs) and to identify epitope escape mutants. Finally, our data show that both natural infection and vaccination could induce multi-functional T cell responses with overall T cell responses remaining despite the identification of escape mutations. Graphical Yin et al. utilize two informative systems for evaluating overall T cell responses to SARS-CoV-2 and variants, enabling greater understanding of T cell responses to the virus, cross-reactivity to viral variants and the differences between vaccine- and infection-induced immunity to SARS-CoV-2, and other emerging viruses in the future.

Efficacy of Primary Series AZD1222 (ChAdOx1 nCoV-19) Vaccination Against SARS-CoV-2 Variants of Concern: Final Analysis of a Randomized, Placebo-controlled, Phase 1b/2 Study in South African Adults (COV005)

COVID-19 vaccine efficacy (VE) has been observed to vary against antigenically distinct SARS-CoV-2 variants of concern (VoC). Here we report the final analysis of VE and safety from COV005: a phase 1b/2, multicenter, double-blind, randomized, placebo-controlled study of primary series AZD1222 (ChAdOx1 nCoV-19) vaccination in South African adults aged 18–65 years. South Africa's first, second, and third waves of SARS-CoV-2 infections were respectively driven by the ancestral SARS-CoV-2 virus (wild type, WT), and SARS-CoV-2 Beta and Delta VoCs. VE against asymptomatic and symptomatic infection was 90.6% for WT, 6.7% for Beta and 77.1% for Delta. No cases of severe COVID-19 were documented ahead of unblinding. Safety was consistent with the interim analysis, with no new safety concerns identified. Notably, South Africa's Delta wave occurred ≥ 9 months after primary series vaccination, suggesting that primary series AZD1222 vaccination offers a good durability of protection, potentially due to an anamnestic response. Clinical trial identifier: CT.gov NCT04444674

Immunisation with purified Coxiella burnetii phase I lipopolysaccharide confers partial protection in mice independently of co-administered adenovirus vectored vaccines.

Q fever is a highly infectious zoonosis caused by the Gram-negative bacterium Coxiella burnetii. The worldwide distribution of Q fever suggests a need for vaccines that are more efficacious, affordable, and does not induce severe adverse reactions in vaccine recipients with pre-existing immunity against Q fever. Potential Q fever vaccine antigens include lipopolysaccharide (LPS) and several C. burnetii surface proteins. Antibodies elicited by purified C. burnetii lipopolysaccharide (LPS) correlate with protection against Q fever, while antigens encoded by adenoviral vectored vaccines can induce cellular immune responses which aid clearing of intracellular pathogens. In the present study, the immunogenicity and the protection induced by adenoviral vectored constructs formulated with the addition of LPS were assessed. Multiple vaccine constructs encoding single or fusion antigens from C. burnetii were synthesised. The adenoviral vectored vaccine constructs alone elicited strong cellular immunity, but this response was not correlative with protection in mice. However, vaccination with LPS was significantly associated with lower weight loss post-bacterial challenge independent of co-administration with adenoviral vaccine constructs, supporting further vaccine development based on LPS.

COVID-19 vaccine effectiveness and variants in Nepal: study protocol for a test-negative case-control study with SARS-CoV-2 genetic sequencing.

INTRODUCTION: Inactivated, viral vector and mRNA vaccines have been used in the Nepali COVID-19 vaccination programme but there is little evidence on the effectiveness of these vaccines in this setting. The aim of this study is to describe COVID-19 vaccine effectiveness in Nepal and provide information on infections with SARS-CoV-2 variants. METHODS AND ANALYSIS: This is a hospital-based, prospective test-negative case-control study conducted at Patan Hospital, Kathmandu. All patients >18 years of age presenting to Patan Hospital with COVID-19-like symptoms who have received a COVID-19 antigen/PCR test are eligible for inclusion. The primary outcome is vaccine effectiveness of licensed COVID-19 vaccines against laboratory-confirmed COVID-19 disease.After enrolment, information will be collected on vaccine status, date of vaccination, type of vaccine, demographics and other medical comorbidities. The primary outcome of interest is laboratory-confirmed SARS-CoV-2 infection. Cases (positive for SARS-CoV-2) and controls (negative for SARS-CoV-2) will be enrolled in a 1:4 ratio. Vaccine effectiveness against COVID-19 disease will be analysed by comparing vaccination status with SARS-CoV-2 test results.Positive SARS-CoV-2 samples will be sequenced to identify circulating variants and estimate vaccine effectiveness against common variants.Measuring vaccine effectiveness and identifying SARS-CoV-2 variants in Nepal will help to inform public health efforts. Describing disease severity in relation to specific SARS-CoV-2 variants and vaccine status will also inform future prevention and care efforts. ETHICS AND DISSEMINATION: Ethical approval was obtained from the University of Oxford Tropical Ethics Committee (OxTREC) (ref: 561-21) and the Patan Academy of Health Sciences Institutional Review Board (ref: drs2111121578). The protocol and supporting study documents were approved for use by the Nepal Health Research Council (NHRC 550-2021). Results will be disseminated in peer-reviewed journals and to the public health authorities in Nepal.

Evolution of long-term vaccine induced and hybrid immunity in healthcare workers after different COVID19 vaccine regimens: a longitudinal cohort study

Background Both infection and vaccination, alone or in combination, generate antibody and T cell responses against SARS-CoV-2. However, the maintenance of such responses – and hence protection from disease – requires careful characterisation. In a large prospective study of UK healthcare workers (Protective immunity from T cells in Healthcare workers (PITCH), within the larger SARS-CoV-2 immunity & reinfection evaluation (SIREN) study) we previously observed that prior infection impacted strongly on subsequent cellular and humoral immunity induced after long and short dosing intervals of BNT162b2 (Pfizer/BioNTech) vaccination. Methods Here, we report longer follow up of 684 HCWs in this cohort over 6-9 months following two doses of BNT162b2 or AZD1222 (Oxford/AstraZeneca) vaccination and up to 6 months following a subsequent mRNA booster vaccination. Findings We make three observations: Firstly, the dynamics of humoral and cellular responses differ;binding and neutralising antibodies declined whereas T and memory B cell responses were maintained after the second vaccine dose. Secondly, vaccine boosting restored IgG levels, broadened neutralising activity against variants of concern including omicron BA.1, BA.2 and BA.5, and boosted T cell responses above the 6-month level post dose 2. Thirdly, prior infection maintained its impact driving larger and broader T cell responses compared with never-infected people – a feature maintained until 6 months after the third dose. Conclusions Broadly cross-reactive T cell responses are well maintained over time – especially in those with combined vaccine and infection-induced immunity ("hybrid” immunity) – and may contribute to continued protection against severe disease. Funding Department for Health and Social Care, Medical Research Council Graphical abstract Moore et al. studied antibody and cellular responses to COVID-19 vaccines before and after dose 3. Antibody responses waned, but T cell responses were well maintained. T cells recognised Omicron variants better and for longer than antibodies. Differences due to vaccine regimen and previous infection evened out over time.

Injection fears and COVID-19 vaccine hesitancy.

BACKGROUND: When vaccination depends on injection, it is plausible that the blood-injection-injury cluster of fears may contribute to hesitancy. Our primary aim was to estimate in the UK adult population the proportion of COVID-19 vaccine hesitancy explained by blood-injection-injury fears. METHODS: In total, 15 014 UK adults, quota sampled to match the population for age, gender, ethnicity, income and region, took part (19 January-5 February 2021) in a non-probability online survey. The Oxford COVID-19 Vaccine Hesitancy Scale assessed intent to be vaccinated. Two scales (Specific Phobia Scale-blood-injection-injury phobia and Medical Fear Survey-injections and blood subscale) assessed blood-injection-injury fears. Four items from these scales were used to create a factor score specifically for injection fears. RESULTS: In total, 3927 (26.2%) screened positive for blood-injection-injury phobia. Individuals screening positive (22.0%) were more likely to report COVID-19 vaccine hesitancy compared to individuals screening negative (11.5%), odds ratio = 2.18, 95% confidence interval (CI) 1.97-2.40, p < 0.001. The population attributable fraction (PAF) indicated that if blood-injection-injury phobia were absent then this may prevent 11.5% of all instances of vaccine hesitancy, AF = 0.11; 95% CI 0.09-0.14, p < 0.001. COVID-19 vaccine hesitancy was associated with higher scores on the Specific Phobia Scale, r = 0.22, p < 0.001, Medical Fear Survey, r = 0.23, p = <0.001 and injection fears, r = 0.25, p < 0.001. Injection fears were higher in youth and in Black and Asian ethnic groups, and explained a small degree of why vaccine hesitancy is higher in these groups. CONCLUSIONS: Across the adult population, blood-injection-injury fears may explain approximately 10% of cases of COVID-19 vaccine hesitancy. Addressing such fears will likely improve the effectiveness of vaccination programmes.

COVID-19 vaccine hesitancy in the UK: the Oxford coronavirus explanations, attitudes, and narratives survey (Oceans) II.

BACKGROUND: Our aim was to estimate provisional willingness to receive a coronavirus 2019 (COVID-19) vaccine, identify predictive socio-demographic factors, and, principally, determine potential causes in order to guide information provision. METHODS: A non-probability online survey was conducted (24th September-17th October 2020) with 5,114 UK adults, quota sampled to match the population for age, gender, ethnicity, income, and region. The Oxford COVID-19 vaccine hesitancy scale assessed intent to take an approved vaccine. Structural equation modelling estimated explanatory factor relationships. RESULTS: 71.7% (n=3,667) were willing to be vaccinated, 16.6% (n=849) were very unsure, and 11.7% (n=598) were strongly hesitant. An excellent model fit (RMSEA=0.05/CFI=0.97/TLI=0.97), explaining 86% of variance in hesitancy, was provided by beliefs about the collective importance, efficacy, side-effects, and speed of development of a COVID-19 vaccine. A second model, with reasonable fit (RMSEA=0.03/CFI=0.93/TLI=0.92), explaining 32% of variance, highlighted two higher-order explanatory factors: 'excessive mistrust' (r=0.51), including conspiracy beliefs, negative views of doctors, and need for chaos, and 'positive healthcare experiences' (r=-0.48), including supportive doctor interactions and good NHS care. Hesitancy was associated with younger age, female gender, lower income, and ethnicity, but socio-demographic information explained little variance (9.8%). Hesitancy was associated with lower adherence to social distancing guidelines. CONCLUSIONS: COVID-19 vaccine hesitancy is relatively evenly spread across the population. Willingness to take a vaccine is closely bound to recognition of the collective importance. Vaccine public information that highlights prosocial benefits may be especially effective. Factors such as conspiracy beliefs that foster mistrust and erode social cohesion will lower vaccine up-take.

Durability of ChAdOx1 nCoV-19 (AZD1222) vaccine and hybrid humoral immunity against variants including omicron BA.1 and BA.4 6 months after vaccination (COV005): a post-hoc analysis of a randomised, phase 1b-2a trial.

BACKGROUND: COVID-19 vaccine rollout is lagging in Africa, where there has been a high rate of SARS-CoV-2 infection. We aimed to evaluate the effect of SARS-CoV-2 infection before vaccination with the ChAdOx-nCoV19 (AZD1222) vaccine on antibody responses through to 180 days. METHODS: We did an unmasked post-hoc immunogenicity analysis after the first and second doses of AZD1222 in a randomised, placebo-controlled, phase 1b-2a study done in seven locations in South Africa. AZD1222 recipients who were HIV-uninfected, were stratified into baseline seropositive or seronegative groups using the serum anti-nucleocapsid (anti-N) immunoglobulin G (IgG) electroluminescence immunoassay to establish SARS-CoV-2 infection before the first dose of AZD1222. Binding IgG to spike (anti-S) and receptor binding domain (anti-RBD) were measured before the first dose (day 0), second dose (day 28), day 42, and day 180. Neutralising antibody (NAb) against SARS-CoV-2 variants D614G, beta, delta, gamma, and A.VOI.V2, and omicron BA1 and BA.4 variants, were measured by pseudovirus assay (day 28, day 42, and day 180). This trial is registered with ClinicalTrials.gov, NCT04444674, and the Pan African Clinicals Trials Registry, PACTR202006922165132. FINDINGS: Of 185 individuals who were randomly assigned to AZD1222, we included 91 individuals who were baseline seropositive and 58 who were baseline seronegative, in the final analysis. In the seropositive group, there was little change of anti-S IgG (and anti-RBD IgG) or neutralising antibody (NAb) titres at day 42 compared with at day 28. Anti-S (and anti-RBD) IgG geometric mean concentrations (GMCs) were higher throughout in the seropositive compared with the seronegative group, including at day 180 (GMCs 517·8 [95% CI 411·3-651·9] vs 82·1 [55·2-122·3] BAU/mL). Also D614G NAb geometric mean titres (GMTs) were higher in the seropositive group than the seronegative group, as was the percentage with titres of at least 185 (80% putative risk reduction threshold [PRRT] against wild-type-alpha COVID-19), including at day 180 (92·0% [74·0-99·0] vs 18·2% [2·3-51·8). Similar findings were observed for beta, A.VOI.V2, and gamma. For delta, BA.1, and BA.4, NAb GMTs and the proportion with titres above the PRRT were substantially higher in the seropositive compared with seronegative group at day 28 and day 42, but no longer differed between the groups by day 180. INTERPRETATION: A single dose of AZD1222 in the general African population, where COVID-19 vaccine coverage is low and SARS-CoV-2 seropositivity is 90%, could enhance the magnitude and quality of antibody responses to SARS-CoV-2. FUNDING: The Bill & Melinda Gates Foundation, the South African Medical Research Council, the UK Research and Innovation, the UK National Institute for Health Research, and the South African Medical Research Council. TRANSLATION: For the Zulu translation of the abstract see Supplementary Materials section.

Evolution of long-term vaccine-induced and hybrid immunity in healthcare workers after different COVID-19 vaccine regimens.

BACKGROUND: Both infection and vaccination, alone or in combination, generate antibody and T cell responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the maintenance of such responses-and hence protection from disease-requires careful characterization. In a large prospective study of UK healthcare workers (HCWs) (Protective Immunity from T Cells in Healthcare Workers [PITCH], within the larger SARS-CoV-2 Immunity and Reinfection Evaluation [SIREN] study), we previously observed that prior infection strongly affected subsequent cellular and humoral immunity induced after long and short dosing intervals of BNT162b2 (Pfizer/BioNTech) vaccination. METHODS: Here, we report longer follow-up of 684 HCWs in this cohort over 6-9 months following two doses of BNT162b2 or AZD1222 (Oxford/AstraZeneca) vaccination and up to 6 months following a subsequent mRNA booster vaccination. FINDINGS: We make three observations: first, the dynamics of humoral and cellular responses differ; binding and neutralizing antibodies declined, whereas T and memory B cell responses were maintained after the second vaccine dose. Second, vaccine boosting restored immunoglobulin (Ig) G levels; broadened neutralizing activity against variants of concern, including Omicron BA.1, BA.2, and BA.5; and boosted T cell responses above the 6-month level after dose 2. Third, prior infection maintained its impact driving larger and broader T cell responses compared with never-infected people, a feature maintained until 6 months after the third dose. CONCLUSIONS: Broadly cross-reactive T cell responses are well maintained over time-especially in those with combined vaccine and infection-induced immunity ("hybrid" immunity)-and may contribute to continued protection against severe disease. FUNDING: Department for Health and Social Care, Medical Research Council.

T-cell responses induced by ChAdOx1 nCoV-19 (AZD1222) vaccine to wild-type severe acute respiratory syndrome coronavirus 2 among people with and without HIV in South Africa.

OBJECTIVES: This study aimed to investigate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T-cell responses 14 days after single-dose ChAdOx1 nCoV-19 (AZD1222) vaccination in black Africans with and without HIV in South Africa, as well as determine the effect of AZD1222 vaccination on cell-mediated immune responses in people with HIV (PWH) with prior SARS-CoV-2 infection. METHODS: A total of 70 HIV-uninfected people and 104 PWH were prospectively enrolled in the multicentre, randomized, double-blinded, placebo-controlled, phase Ib/IIa trial (COV005). Peripheral blood mononuclear cells (PBMCs) were collected from trial participants 14 days after receipt of first dose of study treatment (placebo or AZD1222 vaccine). T-cell responses against the full-length spike (FLS) glycoprotein of wild-type SARS-CoV-2 and mutated S-protein regions found in the Alpha, Beta and Delta variants were assessed using an ex-vivo ELISpot assay. RESULTS: Among AZD1222 recipients without preceding SARS-CoV-2 infection, T-cell responses to FLS of wild-type SARS-CoV-2 were similarly common in PWH and HIV-uninfected people (30/33, 90.9% vs. 16/21, 76.2%; P = 0.138); and magnitude of response was similar among responders (78 vs. 56 SFCs/106 PBMCs; P = 0.255). Among PWH, AZD1222 vaccinees with prior SARS-CoV-2 infection, displayed a heightened T-cell response magnitude compared with those without prior infection (186 vs. 78 SFCs/106 PBMCs; P = 0.001); and similar response rate (14/14, 100% vs. 30/33, 90.9%; P = 0.244). CONCLUSION: Our results indicate comparable T-cell responses following AZD1222 vaccination in HIV-uninfected people and PWH on stable antiretroviral therapy. Our results additionally show that hybrid immunity acquired through SARS-CoV-2 infection and AZD1222 vaccination, induce a heightened T-cell response.

Booster vaccination against SARS-CoV-2 induces potent immune responses in people with HIV.

BACKGROUND: People with HIV on antiretroviral therapy with good CD4 T cell counts make effective immune responses following vaccination against SARS-CoV-2. There are few data on longer term responses and the impact of a booster dose. METHODS: Adults with HIV were enrolled into a single arm open label study. Two doses of ChAdOx1 nCoV-19 were followed twelve months later by a third heterologous vaccine dose. Participants had undetectable viraemia on ART and CD4 counts >350 cells/µl. Immune responses to the ancestral strain and variants of concern were measured by anti-spike IgG ELISA, MesoScale Discovery (MSD) anti-spike platform, ACE-2 inhibition, Activation Induced Marker (AIM) assay and T cell proliferation. FINDINGS: 54 participants received two doses of ChAdOx1 nCoV-19. 43 received a third dose (42 with BNT162b2; 1 with mRNA-1273) one year after the first dose. After the third dose, total anti-SARS-CoV-2 spike IgG titres (MSD), ACE-2 inhibition and IgG ELISA results were significantly higher compared to Day 182 titres (P < 0.0001 for all three). SARS-CoV-2 specific CD4+ T cell responses measured by AIM against SARS-CoV-2 S1 and S2 peptide pools were significantly increased after a third vaccine compared to 6 months after a first dose, with significant increases in proliferative CD4 + and CD8+ T cell responses to SARS-CoV-2 S1 and S2 after boosting. Responses to Alpha, Beta, Gamma, and Delta variants were boosted, although to a lesser extent for Omicron. CONCLUSIONS: In PWH receiving a third vaccine dose, there were significant increases in B and T cell immunity, including to known VOCs.

Human leukocyte antigen alleles associate with COVID-19 vaccine immunogenicity and risk of breakthrough infection.

SARS-CoV-2 vaccine immunogenicity varies between individuals, and immune responses correlate with vaccine efficacy. Using data from 1,076 participants enrolled in ChAdOx1 nCov-19 vaccine efficacy trials in the United Kingdom, we find that inter-individual variation in normalised antibody responses against SARS-CoV-2 spike (S) and its receptor binding domain (RBD) at 28 days following first vaccination shows genome-wide significant association with major histocompatibility complex (MHC) class II alleles. The most statistically significant association with higher levels of anti-RBD antibody was HLA-DQB1*06 (P = 3.2 × 10-9), which we replicate in 1,677 additional vaccinees. Individuals carrying HLA-DQB1*06 alleles were less likely to experience PCR-confirmed breakthrough infection during the ancestral SARS-CoV-2 virus and subsequent Alpha-variant waves compared with non-carriers (HR 0.63, 0.42-0.93, P = 0.02). We identify a distinct S-derived peptide that is predicted to bind differentially to HLA-DQB1*06 compared with other similar alleles, and find evidence of increased spike-specific memory B-cell responses in HLA-DQB1*06 carriers at 84 days following first vaccination. Our results demonstrate association of HLA type with COVID-19 vaccine antibody response and risk of breakthrough infection, with implications for future vaccine design and implementation.

Persistence of the immune response after two doses of ChAdOx1 nCov-19 (AZD1222): 1 year of follow-up of two randomized controlled trials.

The trajectory of immune responses following the primary dose series determines the decline in vaccine effectiveness over time. Here we report on maintenance of immune responses during the year following a two-dose schedule of ChAdOx1 nCoV-19/AZD1222, in the absence of infection, and also explore the decay of antibody after infection. Total spike-specific IgG antibody titres were lower with two low doses of ChAdOx1 nCoV-19 vaccines (two low doses) (P = 0.0006) than with 2 standard doses (the approved dose) or low dose followed by standard dose vaccines regimens. Longer intervals between first and second doses resulted in higher antibody titres (P < 0.0001); however, there was no evidence that the trajectory of antibody decay differed by interval or by vaccine dose, and the decay of IgG antibody titres followed a similar trajectory after a third dose of ChAdOx1 nCoV-19. Trends in post-infection samples were similar with an initial rapid decay in responses but good persistence of measurable responses thereafter. Extrapolation of antibody data, following two doses of ChAdOx1 nCov-19, demonstrates a slow rate of antibody decay with modelling, suggesting that antibody titres are well maintained for at least 2 years. These data suggest a persistent immune response after two doses of ChAdOx1 nCov-19 which will likely have a positive impact against serious disease and hospitalization.

Polio eradication: Addressing the hurdles on the last mile.

1988, the World Health Assembly committed to eradicate poliomyelitis, a viral disease that can cause permanent paralysis. Today, only type 1 of the three wild poliovirus types remains circulating in limited geographic areas following widespread use of different poliovirus vaccines. While we are close to zero new cases of wild polio, it is a fragile situation, and there are many remaining and new hurdles to overcome. Here, experts discuss how to address them.

A delicate balance between antibody evasion and ACE2 affinity for Omicron BA.2.75.

Variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have caused successive global waves of infection. These variants, with multiple mutations in the spike protein, are thought to facilitate escape from natural and vaccine-induced immunity and often increase in affinity for ACE2. The latest variant to cause concern is BA.2.75, identified in India where it is now the dominant strain, with evidence of wider dissemination. BA.2.75 is derived from BA.2 and contains four additional mutations in the receptor-binding domain (RBD). Here, we perform an antigenic and biophysical characterization of BA.2.75, revealing an interesting balance between humoral evasion and ACE2 receptor affinity. ACE2 affinity for BA.2.75 is increased 9-fold compared with BA.2; there is also evidence of escape of BA.2.75 from immune serum, particularly that induced by Delta infection, which may explain the rapid spread in India, where where there is a high background of Delta infection. ACE2 affinity appears to be prioritized over greater escape.

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

BACKGROUND: Vaccination of children and young people against SARS-CoV-2 is recommended in some countries. Scarce data have been published on immune responses induced by COVID-19 vaccines in people younger than 18 years compared with the same data that are available in adults. METHODS: COV006 is a phase 2, single-blind, randomised, controlled trial of ChAdOx1 nCoV-19 (AZD1222) in children and adolescents at four trial sites in the UK. Healthy participants aged 6-17 years, who did not have a history of chronic respiratory conditions, laboratory-confirmed COVID-19, or previously received capsular group B meningococcal vaccine (the control), were randomly assigned to four groups (4:1:4:1) to receive two intramuscular doses of 5 × 1010 viral particles of ChAdOx1 nCoV-19 or control, 28 days or 84 days apart. Participants, clinical investigators, and the laboratory team were masked to treatment allocation. Study groups were stratified by age, and participants aged 12-17 years were enrolled before those aged 6-11 years. Due to the restrictions in the use of ChAdOx1 nCoV-19 in people younger than 30 years that were introduced during the study, only participants aged 12-17 years who were randomly assigned to the 28-day interval group had received their vaccinations at the intended interval (day 28). The remaining participants received their second dose at day 112. The primary outcome was assessment of safety and tolerability in the safety population, which included all participants who received at least one dose of the study drug. The secondary outcome was immunogenicity, which was assessed in participants who were seronegative to the nucleocapsid protein at baseline and received both prime and boost vaccine. This study is registered with ISRCTN (15638344). FINDINGS: Between Feb 15 and April 2, 2021, 262 participants (150 [57%] participants aged 12-17 years and 112 [43%] aged 6-11 years; due to the change in the UK vaccination policy, the study terminated recruitment of the younger age group before the planned number of participants had been enrolled) were randomly assigned to receive vaccination with two doses of either ChAdOx1 nCoV-19 (n=211 [n=105 at day 28 and n=106 at day 84]) or control (n=51 [n=26 at day 28 and n=25 at day 84]). One participant in the ChAdOx1 nCoV-19 day 28 group in the younger age bracket withdrew their consent before receiving a first dose. Of the participants who received ChAdOx1 nCoV-19, 169 (80%) of 210 participants reported at least one solicited local or systemic adverse event up to 7 days following the first dose, and 146 (76%) of 193 participants following the second dose. No serious adverse events related to ChAdOx1 nCoV-19 administration were recorded by the data cutoff date on Oct 28, 2021. Of the participants who received at least one dose of ChAdOx1 nCoV-19, there were 128 unsolicited adverse events up to 28 days after vaccination reported by 83 (40%) of 210 participants. One participant aged 6-11 years receiving ChAdOx1 nCoV-19 reported a grade 4 fever of 40·2°C on day 1 following first vaccination, which resolved within 24 h. Pain and tenderness were the most common local solicited adverse events for all the ChAdOx1 nCoV-19 and capsular group B meningococcal groups following both doses. Of the 242 participants with available serostatus data, 14 (6%) were seropositive at baseline. Serostatus data were not available for 20 (8%) of 262 participants. Among seronegative participants who received ChAdOx1 nCoV-19, anti-SARS-CoV-2 IgG and pseudoneutralising antibody titres at day 28 after the second dose were higher in participants aged 12-17 years with a longer interval between doses (geometric means of 73 371 arbitrary units [AU]/mL [95% CI 58 685-91 733] and 299 half-maximal inhibitory concentration [IC50; 95% CI 230-390]) compared with those aged 12-17 years who received their vaccines 28 days apart (43 280 AU/mL [95% CI 35 852-52 246] and 150 IC50 [95% CI 116-194]). Humoral responses were higher in those aged 6-11 years than in those aged 12-17 years receiving their second dose at the same 112-day interval (geometric mean ratios 1·48 [95% CI 1·07-2·07] for anti-SARS-CoV-2 IgG and 2·96 [1·89-4·62] for pseudoneutralising antibody titres). Cellular responses peaked after a first dose of ChAdOx1 nCoV-19 across all age and interval groups and remained above baseline after a second vaccination. INTERPRETATION: ChAdOx1 nCoV-19 is well tolerated and immunogenic in children aged 6-17 years, inducing concentrations of antibody that are similar to those associated with high efficacy in phase 3 studies in adults. No safety concerns were raised in this trial. FUNDING: AstraZeneca and the UK Department of Health and Social Care through the UK National Institute for Health and Care Research.

Effect of the of 10-valent pneumococcal conjugate vaccine in Nepal 4 years after introduction: an observational cohort study.

BACKGROUND: In Nepal, Streptococcus pneumoniae (pneumococcus) is a common cause of bacterial pneumonia in children, and is a major health concern. There are few data on the effect of vaccination on the disease or colonisation with pneumococci in the nasopharynx of children in this setting. The 10-valent pneumococcal conjugate vaccine (PCV10) was introduced into the routine infant immunisation schedule in Nepal in 2015. We aimed to investigate the effect of the introduction of PCV10 on pneumococcal carriage and disease in children in Nepal. METHODS: We did an observational cohort study in children in Nepal. The hospital surveillance study took place in Patan Hospital, Kathmandu, and community studies in healthy children took place in Kathmandu and Okhaldhunga district. For the surveillance study, all children admitted to Patan Hospital between March 20, 2014, and Dec 31, 2019, aged between 2 months and 14 years with clinician-suspected pneumonia, were eligible for enrolment. For the community study, healthy children aged 0-8 weeks, 6-23 months, and 24-59 months were recruited from Kathmandu, and healthy children aged 6-23 months were recruited from Okhaldhunga. We assessed the programmatic effect of PCV10 introduction using surveillance for nasopharyngeal colonisation, pneumonia, and invasive bacterial disease from 1·5 years before vaccine introduction and 4·5 years after vaccine introduction. For the surveillance study, nasopharyngeal swabs, blood cultures, and chest radiographs were obtained from children admitted to Patan Hospital with suspected pneumonia or invasive bacterial disease. For the community study, nasopharyngeal swabs were obtained from healthy children in the urban and rural settings. Pneumonia outcomes were analysed using log-binomial models and adjusted prevalence ratios (aPR) comparing each calendar year after the introduction of the vaccine into the national programme with the pre-vaccine period (2014-15), adjusted for calendar month, age, and sex. FINDINGS: Between March 20, 2014, and Dec 31, 2019, we enrolled 2051 children with suspected pneumonia, and 11 354 healthy children (8483 children aged 6-23 months, 761 aged 24-59 months, and 2110 aged 0-8 weeks) to assess nasopharyngeal colonisation. Among clinical pneumonia cases younger than 2 years, vaccine serotype carriage declined 82% (aPR 0·18 [95% CI 0·07-0·50]) by 2019. There was no decrease in vaccine serotype carriage in cases among older unvaccinated age groups. Carriage of the additional serotypes in PCV13 was 2·2 times higher by 2019 (aPR 2·17 [95% CI 1·16-4·05]), due to increases in serotypes 19A and 3. Vaccine serotype carriage in healthy children declined by 75% in those aged 6-23 months (aPR 0·25 [95% CI 0·19-0·33]) but not in those aged 24-59 months (aPR 0·59 [0·29-1·19]). A decrease in overall vaccine serotype carriage of 61% by 2019 (aPR 0·39 [95% CI 0·18-0·85]) was also observed in children younger than 8 weeks who were not yet immunised. Carriage of the additional PCV13 serotypes in children aged 6-23 months increased after PCV10 introduction for serotype 3 and 19A, but not for serotype 6A. The proportion of clinical pneumonia cases with endpoint consolidation on chest radiographs declined from 41% in the pre-vaccine period to 25% by 2018, but rose again in 2019 to 36%. INTERPRETATION: The introduction of the PCV10 vaccine into the routine immunisation programme in Nepal has reduced vaccine serotype carriage in both healthy children and children younger than 2 years with pneumonia. Increases in serotypes 19A and 3 highlight the importance of continued surveillance to monitor the effect of vaccine programmes. This analysis demonstrates a robust approach to assessing vaccine effect in situations in which pneumococcal disease endpoint effectiveness studies are not possible. FUNDING: Gavi, the Vaccine Alliance and the World Health Organization.