Publications by authors named "Andrew J Pollard"

473 Publications

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

Nat Commun 2021 10 6;12(1):5861. Epub 2021 Oct 6.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.

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.
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http://dx.doi.org/10.1038/s41467-021-25982-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494913PMC
October 2021

Willingness of children and adolescents to have a COVID-19 vaccination: Results of a large whole schools survey in England.

EClinicalMedicine 2021 Sep 27:101144. Epub 2021 Sep 27.

Department of Psychiatry, University of Oxford, Warneford Lane, Oxford OX3 7JX, UK.

Background: Vaccine hesitancy has affected COVID-19 adult vaccination programs in many countries. Data on hesitancy amongst child and adolescent populations is largely confined to parent opinion. We investigated the characteristics of vaccine hesitant children and adolescents using results from a large, school-based self-report survey of the willingness to have a COVID-19 vaccination in students aged 9 -18 years in England.

Methods: Data from the OxWell Student Survey on mental health, life experiences and behaviours were used, collected from four counties across England. Local authority partners recruited schools. The vaccine hesitancy question gave six response options and were clustered to inform delivery: eager and willing were categorised as vaccination 'opt-in', don't know and not bothered categorised as 'undecided', and unwilling and anti-vaccination categorised as 'opt-out'. We conducted a multinomial regression to determine associations between vaccine hesitancy and sociodemographic, health behaviour and social connection variables.

Findings: 27,910 students from 180 schools answered the vaccine hesitancy question between 14th May and 21st July 2021, of whom 13984 (50.1%) would opt-in to take a vaccination, 10322 (37.0%) were undecided, and 3604 (12.9%) would opt-out. A lower percentage of younger students reported that they would opt-in to vaccination, for example, 35.7% of 9-year-olds and 51.3% of 13-year-olds compared to 77.8% of 17-year-olds would opt-in to take a vaccination. Students who were 'opt-out' or 'undecided' (a combined 'vaccine hesitant' group) were more likely to come from deprived socioeconomic contexts with higher rates of home rental versus home ownership and their school locations were more likely to be in areas of greater deprivation. They were more likely to smoke or vape, spend longer on social media, feel that they did not belong in their school community but had lower levels of anxiety and depression. The vaccine hesitant students- the undecided and opt-out groups- were similar in profile, although the opt-out students had higher reported confirmed or probable previous COVID-19 infection than the opt-in group, whereas those undecided, did not.

Interpretation: If government vaccination strategies move towards vaccinating younger school-aged students, efforts to increase vaccination uptake may be necessary. Compared with students who would opt-in, those who were vaccine hesitant had greater indicators of social deprivation and felt a lack of community cohesion by not feeling a sense of belonging at their school. There were indications that those students who would opt-out had higher levels of marginalisation and mistrust. If programmes are rolled out, focus on hesitant younger students will be important, targeting more marginalised and deprived young people with information from trusted sources utilising social media; improving access to vaccination centres with provision both in and outside school; and addressing fears and worries about the effects of the vaccine. The main limitation of this study is that the participant group may not be wholly representative of England or the UK, which may bias population-level estimates of willingness to be vaccinated.

Funding: The Westminster Foundation, the National Institute for Health Research (NIHR) Applied Research Collaboration Oxford and Thames Valley at Oxford Health NHS Foundation Trust and the NIHR Oxford Health Biomedical Research Centre.
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http://dx.doi.org/10.1016/j.eclinm.2021.101144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482530PMC
September 2021

Correlates of protection against symptomatic and asymptomatic SARS-CoV-2 infection.

Nat Med 2021 Sep 29. Epub 2021 Sep 29.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.

The global supply of COVID-19 vaccines remains limited. An understanding of the immune response that is predictive of protection could facilitate rapid licensure of new vaccines. Data from a randomized efficacy trial of the ChAdOx1 nCoV-19 (AZD1222) vaccine in the United Kingdom was analyzed to determine the antibody levels associated with protection against SARS-CoV-2. Binding and neutralizing antibodies at 28 days after the second dose were measured in infected and noninfected vaccine recipients. Higher levels of all immune markers were correlated with a reduced risk of symptomatic infection. A vaccine efficacy of 80% against symptomatic infection with majority Alpha (B.1.1.7) variant of SARS-CoV-2 was achieved with 264 (95% CI: 108, 806) binding antibody units (BAU)/ml: and 506 (95% CI: 135, not computed (beyond data range) (NC)) BAU/ml for anti-spike and anti-RBD antibodies, and 26 (95% CI: NC, NC) international unit (IU)/ml and 247 (95% CI: 101, NC) normalized neutralization titers (NF) for pseudovirus and live-virus neutralization, respectively. Immune markers were not correlated with asymptomatic infections at the 5% significance level. These data can be used to bridge to new populations using validated assays, and allow extrapolation of efficacy estimates to new COVID-19 vaccines.
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http://dx.doi.org/10.1038/s41591-021-01540-1DOI Listing
September 2021

Salmonella Typhi stool shedding by enteric fever patients and asymptomatic chronic carriers in an endemic urban setting.

J Infect Dis 2021 Sep 29. Epub 2021 Sep 29.

icddr,b, (International Centre for Diarrhoeal Disease Research, Bangladesh), Dhaka, Bangladesh.

The burden of Salmonella Typhi shedding in stool and its contribution to transmission in endemic settings is unknown. During passive surveillance S. Typhi shedding was seen during convalescence in 332 bacteremic typhoid patients although none persisted at one-year follow-up. Anti-Vi-IgG titres were measured in age-stratified cohort of serosurveillance participants. Systematic stool sampling of 303 participants with high anti-Vi-IgG titres identified one asymptomatic carrier shedding. These findings suggest ongoing S. Typhi transmission in this setting is more likely to occur from acute convalescent cases although better approaches are needed to identify true chronic carriers in the community to enable typhoid elimination.
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http://dx.doi.org/10.1093/infdis/jiab476DOI Listing
September 2021

Recent Advances in Lipopolysaccharide-Based Glycoconjugate Vaccines.

Expert Rev Vaccines 2021 Sep 22. Epub 2021 Sep 22.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Oxford, UK.

Introduction: The public health burden caused by pathogenic Gram-negative bacteria is increasingly prominent due to antimicrobial resistance. The surface carbohydrates are potential antigens for vaccines against Gram-negative bacteria. The enhanced immunogenicity of the O-specific polysaccharide (O-SP) moiety of LPS when coupled to a carrier protein may protect against bacterial pathogens. However, because of the toxic lipid A moiety and relatively high costs of O-SP isolation, LPS has not been a popular vaccine antigen until recently.

Areas Covered: In this review, we discuss the rationales for developing LPS-based glycoconjugate vaccines, principles of glycoconjugate-induced immunity, and highlight the recent developments and challenges faced by LPS-based glycoconjugate vaccines.

Expert Opinion: Advances in LPS harvesting, LPS chemical synthesis, and newer carrier proteins in the past decade have propelled LPS-based glycoconjugate vaccines towards further development, through to clinical evaluation. The development of LPS-based glycoconjugates offers a new horizon for vaccine prevention of Gram-negative bacterial infection.
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http://dx.doi.org/10.1080/14760584.2021.1984889DOI Listing
September 2021

Typhoid conjugate vaccine in Africa and Asia: Status of clinical evaluation and vaccine introduction.

J Infect Dis 2021 Sep 16. Epub 2021 Sep 16.

Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, 21201, USA.

The disease burden of typhoid fever remains high in endemic areas in Asia and Africa, especially in children. Recent clinical trials conducted by the Typhoid Vaccine Acceleration Consortium show typhoid conjugate vaccine (TCV) to be safe, immunogenic, and efficacious at preventing blood culture-confirmed typhoid fever in African and Asian children. Pakistan, Liberia, and Zimbabwe recently introduced TCV through campaigns and routine childhood immunizations, providing protection for this vulnerable population. It is essential to continue this momentum while simultaneously filling data gaps - including typhoid complications - to inform decision-making on TCV introduction. A multidisciplinary approach including surveillance, water, sanitation, and hygiene investments, and large-scale TCV introduction is needed to decrease the burden and mortality of typhoid fever.
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http://dx.doi.org/10.1093/infdis/jiab449DOI Listing
September 2021

A Systematic Review and Meta-analysis of Animal Studies Investigating the Relationship Between Serum Antibody, T Lymphocytes, and Respiratory Syncytial Virus Disease.

J Infect Dis 2021 Sep 15. Epub 2021 Sep 15.

Oxford Vaccine Group, Paediatrics, University of Oxford, Oxford, United Kingdom.

Background: Respiratory syncytial virus (RSV) infections occur in human populations around the globe, causing disease of variable severity, disproportionately affecting infants and older adults (>65 years of age). Immune responses can be protective but also contribute to disease. Experimental studies in animals enable detailed investigation of immune responses, provide insights into clinical questions, and accelerate the development of passive and active vaccination. We aimed to review the role of antibody and T-cell responses in relation to RSV disease severity in animals.

Methods: Systematic review and meta-analysis of animal studies examining the association between T-cell responses/phenotype or antibody titers and severity of RSV disease. The PubMed, Zoological Record, and Embase databases were screened from January 1980 to May 2018 to identify animal studies of RSV infection that assessed serum antibody titer or T lymphocytes with disease severity as an outcome. Sixty-three studies were included in the final review.

Results: RSV-specific antibody appears to protect from disease in mice, but such an effect was less evident in bovine RSV. Strong T-cell, Th1, Th2, Th17, CD4/CD8 responses, and weak Treg responses accompany severe disease in mice.

Conclusions: Murine studies suggest that measures of T-lymphocyte activity (particularly CD4 and CD8 T cells) may be predictive biomarkers of severity. Further inquiry is merited to validate these results and assess relevance as biomarkers for human disease.
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http://dx.doi.org/10.1093/infdis/jiab370DOI Listing
September 2021

Reactogenicity and immunogenicity after a late second dose or a third dose of ChAdOx1 nCoV-19 in the UK: a substudy of two randomised controlled trials (COV001 and COV002).

Lancet 2021 09 1;398(10304):981-990. Epub 2021 Sep 1.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.

Background: COVID-19 vaccine supply shortages are causing concerns about compromised immunity in some countries as the interval between the first and second dose becomes longer. Conversely, countries with no supply constraints are considering administering a third dose. We assessed the persistence of immunogenicity after a single dose of ChAdOx1 nCoV-19 (AZD1222), immunity after an extended interval (44-45 weeks) between the first and second dose, and response to a third dose as a booster given 28-38 weeks after the second dose.

Methods: In this substudy, volunteers aged 18-55 years who were enrolled in the phase 1/2 (COV001) controlled trial in the UK and had received either a single dose or two doses of 5 × 10 viral particles were invited back for vaccination. Here we report the reactogenicity and immunogenicity of a delayed second dose (44-45 weeks after first dose) or a third dose of the vaccine (28-38 weeks after second dose). Data from volunteers aged 18-55 years who were enrolled in either the phase 1/2 (COV001) or phase 2/3 (COV002), single-blinded, randomised controlled trials of ChAdOx1 nCoV-19 and who had previously received a single dose or two doses of 5 × 10 viral particles are used for comparison purposes. COV001 is registered with ClinicalTrials.gov, NCT04324606, and ISRCTN, 15281137, and COV002 is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137, and both are continuing but not recruiting.

Findings: Between March 11 and 21, 2021, 90 participants were enrolled in the third-dose boost substudy, of whom 80 (89%) were assessable for reactogenicity, 75 (83%) were assessable for evaluation of antibodies, and 15 (17%) were assessable for T-cells responses. The two-dose cohort comprised 321 participants who had reactogenicity data (with prime-boost interval of 8-12 weeks: 267 [83%] of 321; 15-25 weeks: 24 [7%]; or 44-45 weeks: 30 [9%]) and 261 who had immunogenicity data (interval of 8-12 weeks: 115 [44%] of 261; 15-25 weeks: 116 [44%]; and 44-45 weeks: 30 [11%]). 480 participants from the single-dose cohort were assessable for immunogenicity up to 44-45 weeks after vaccination. Antibody titres after a single dose measured approximately 320 days after vaccination remained higher than the titres measured at baseline (geometric mean titre of 66·00 ELISA units [EUs; 95% CI 47·83-91·08] vs 1·75 EUs [1·60-1·93]). 32 participants received a late second dose of vaccine 44-45 weeks after the first dose, of whom 30 were included in immunogenicity and reactogenicity analyses. Antibody titres were higher 28 days after vaccination in those with a longer interval between first and second dose than for those with a short interval (median total IgG titre: 923 EUs [IQR 525-1764] with an 8-12 week interval; 1860 EUs [917-4934] with a 15-25 week interval; and 3738 EUs [1824-6625] with a 44-45 week interval). Among participants who received a third dose of vaccine, antibody titres (measured in 73 [81%] participants for whom samples were available) were significantly higher 28 days after a third dose (median total IgG titre: 3746 EUs [IQR 2047-6420]) than 28 days after a second dose (median 1792 EUs [IQR 899-4634]; Wilcoxon signed rank test p=0·0043). T-cell responses were also boosted after a third dose (median response increased from 200 spot forming units [SFUs] per million peripheral blood mononuclear cells [PBMCs; IQR 127-389] immediately before the third dose to 399 SFUs per milion PBMCs [314-662] by day 28 after the third dose; Wilcoxon signed rank test p=0·012). Reactogenicity after a late second dose or a third dose was lower than reactogenicity after a first dose.

Interpretation: An extended interval before the second dose of ChAdOx1 nCoV-19 leads to increased antibody titres. A third dose of ChAdOx1 nCoV-19 induces antibodies to a level that correlates with high efficacy after second dose and boosts T-cell responses.

Funding: UK Research and Innovation, Engineering and Physical Sciences Research Council, National Institute for Health Research, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research Oxford Biomedical Research Centre, Chinese Academy of Medical Sciences Innovation Fund for Medical Science, Thames Valley and South Midlands NIHR Clinical Research Network, AstraZeneca, and Wellcome.
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http://dx.doi.org/10.1016/S0140-6736(21)01699-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409975PMC
September 2021

Rapid monitoring of graphene exfoliation using NMR proton relaxation.

Nanoscale 2021 Sep 2;13(34):14518-14524. Epub 2021 Sep 2.

National Physical Laboratory, Hampton Road, Teddington, TW11 0LW, UK.

Graphene is now being produced on an industrial scale and there is a pressing need for rapid in-line measurements of particle size for Quality Assurance and Quality Control (QA/QC). Standardised characterisation techniques such as electron microscopy and scanning probe microscopy can be time consuming and may require pre-processing steps and/or solvent elimination prior to measurements. Herein, we demonstrate the use of nuclear magnetic resonance (NMR) proton relaxation as a powerful method for monitoring the sonication assisted liquid phase exfoliation of graphene. This technique requires little or no sample preparation and the resulting spin-spin relaxation time showed a strong correlation with particle size, exfoliation yield and specific surface area measurements. As the NMR proton relaxation method is rapid, inexpensive, and can potentially be operated in-line, it shows great promise to become a valuable QA/QC method for graphene production methods in liquid.
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http://dx.doi.org/10.1039/d1nr03361aDOI Listing
September 2021

Impact of Vaccination on Haemophilus influenzae Type b Carriage in Healthy Children Less Than 5 Years of Age in an Urban Population in Nepal.

J Infect Dis 2021 Sep;224(Supplement_3):S267-S274

Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the National Institute for Health Research Oxford Biomedical Research Centre, Oxford, United Kingdom.

Background: Reduction in detection of asymptomatic carriage of Haemophilus influenzae type b (Hib) can be used to assess vaccine impact. In Nepal, routine vaccination against Hib in children at 6, 10, and 14 weeks of age was introduced in 2009. Before vaccine introduction, Hib carriage was estimated at 5.0% among children aged <13 years in Nepal, with higher rates among children under 5. Large-scale evaluation of Hib carriage in children has not been investigated since the introduction of the pentavalent diphtheria-tetanus-pertussis/Hib/hepatitis B (DTP-Hib-HepB) vaccine in Nepal.

Methods: A total of 666 oropharyngeal swabs were collected between August and December 2018 from healthy children between 6 months and 5 years of age attending the vaccination clinic at Patan Hospital, Kathmandu, Nepal. Of these 666 swabs, 528 (79.3%) were tested for Hib by culture. Demographic and vaccination data were collected.

Results: Among 528 swabs tested for Hib, 100% came from fully vaccinated children. No swabs were positive for Hib (95% confidence interval, .0-.7). The absence of Hib in 2018 suggests vaccine-induced protection against Hib carriage 9 years after vaccine introduction.

Conclusions: Following 3 doses of pentavalent DTP-Hib-HepB vaccine, Hib carriage in children under the age of 5 years in Nepal is no longer common. Ongoing high coverage with Hib vaccine in early childhood is expected to maintain protection against Hib disease in Nepal.
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http://dx.doi.org/10.1093/infdis/jiab072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409530PMC
September 2021

Distinct patterns of within-host virus populations between two subgroups of human respiratory syncytial virus.

Nat Commun 2021 08 26;12(1):5125. Epub 2021 Aug 26.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.

Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in young children globally, but little is known about within-host RSV diversity. Here, we characterised within-host RSV populations using deep-sequencing data from 319 nasopharyngeal swabs collected during 2017-2020. RSV-B had lower consensus diversity than RSV-A at the population level, while exhibiting greater within-host diversity. Two RSV-B consensus sequences had an amino acid alteration (K68N) in the fusion (F) protein, which has been associated with reduced susceptibility to nirsevimab (MEDI8897), a novel RSV monoclonal antibody under development. In addition, several minor variants were identified in the antigenic sites of the F protein, one of which may confer resistance to palivizumab, the only licensed RSV monoclonal antibody. The differences in within-host virus populations emphasise the importance of monitoring for vaccine efficacy and may help to explain the different prevalences of monoclonal antibody-escape mutants between the two subgroups.
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http://dx.doi.org/10.1038/s41467-021-25265-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390747PMC
August 2021

A Bayesian approach for estimating typhoid fever incidence from large-scale facility-based passive surveillance data.

Stat Med 2021 Aug 24. Epub 2021 Aug 24.

Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, USA.

Decisions about typhoid fever prevention and control are based on estimates of typhoid incidence and their uncertainty. Lack of specific clinical diagnostic criteria, poorly sensitive diagnostic tests, and scarcity of accurate and complete datasets contribute to difficulties in calculating age-specific population-level typhoid incidence. Using data from the Strategic Typhoid Alliance across Africa and Asia program, we integrated demographic censuses, healthcare utilization surveys, facility-based surveillance, and serological surveillance from Malawi, Nepal, and Bangladesh to account for under-detection of cases. We developed a Bayesian approach that adjusts the count of reported blood-culture-positive cases for blood culture detection, blood culture collection, and healthcare seeking-and how these factors vary by age-while combining information from prior published studies. We validated the model using simulated data. The ratio of observed to adjusted incidence rates was 7.7 (95% credible interval [CrI]: 6.0-12.4) in Malawi, 14.4 (95% CrI: 9.3-24.9) in Nepal, and 7.0 (95% CrI: 5.6-9.2) in Bangladesh. The probability of blood culture collection led to the largest adjustment in Malawi, while the probability of seeking healthcare contributed the most in Nepal and Bangladesh; adjustment factors varied by age. Adjusted incidence rates were within or below the seroincidence rate limits of typhoid infection. Estimates of blood-culture-confirmed typhoid fever without these adjustments results in considerable underestimation of the true incidence of typhoid fever. Our approach allows each phase of the reporting process to be synthesized to estimate the adjusted incidence of typhoid fever while correctly characterizing uncertainty, which can inform decision-making for typhoid prevention and control.
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http://dx.doi.org/10.1002/sim.9159DOI Listing
August 2021

Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 in people living with and without HIV in South Africa: an interim analysis of a randomised, double-blind, placebo-controlled, phase 1B/2A trial.

Lancet HIV 2021 09 17;8(9):e568-e580. Epub 2021 Aug 17.

South African Medical Research Council Vaccines and Infectious Diseases Analytics Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; Department of Science and Innovation/National Research Foundation South African Research Chair Initiative in Vaccine Preventable Diseases Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

Background: People living with HIV are at an increased risk of fatal outcome when admitted to hospital for severe COVID-19 compared with HIV-negative individuals. We aimed to assess safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine in people with HIV and HIV-negative individuals in South Africa.

Methods: In this ongoing, double-blind, placebo-controlled, phase 1B/2A trial (COV005), people with HIV and HIV-negative participants aged 18-65 years were enrolled at seven South African locations and were randomly allocated (1:1) with full allocation concealment to receive a prime-boost regimen of ChAdOx1 nCoV-19, with two doses given 28 days apart. Eligibility criteria for people with HIV included being on antiretroviral therapy for at least 3 months, with a plasma HIV viral load of less than 1000 copies per mL. In this interim analysis, safety and reactogenicity was assessed in all individuals who received at least one dose of ChAdOx1 nCov 19 between enrolment and Jan 15, 2021. Primary immunogenicity analyses included participants who received two doses of trial intervention and were SARS-CoV-2 seronegative at baseline. This trial is registered with ClinicalTrials.gov, NCT04444674, and the Pan African Clinicals Trials Registry, PACTR202006922165132.

Findings: Between June 24 and Nov 12, 2020, 104 people with HIV and 70 HIV-negative individuals were enrolled. 102 people with HIV (52 vaccine; 50 placebo) and 56 HIV-negative participants (28 vaccine; 28 placebo) received the priming dose, 100 people with HIV (51 vaccine; 49 placebo) and 46 HIV-negative participants (24 vaccine; 22 placebo) received two doses (priming and booster). In participants seronegative for SARS-CoV-2 at baseline, there were 164 adverse events in those with HIV (86 vaccine; 78 placebo) and 237 in HIV-negative participants (95 vaccine; 142 placebo). Of seven serious adverse events, one severe fever in a HIV-negative participant was definitely related to trial intervention and one severely elevated alanine aminotranferase in a participant with HIV was unlikely related; five others were deemed unrelated. One person with HIV died (unlikely related). People with HIV and HIV-negative participants showed vaccine-induced serum IgG responses against wild-type Wuhan-1 Asp614Gly (also known as D614G). For participants seronegative for SARS-CoV-2 antigens at baseline, full-length spike geometric mean concentration (GMC) at day 28 was 163·7 binding antibody units (BAU)/mL (95% CI 89·9-298·1) for people with HIV (n=36) and 112·3 BAU/mL (61·7-204·4) for HIV-negative participants (n=23), with a rising day 42 GMC booster response in both groups. Baseline SARS-CoV-2 seropositive people with HIV demonstrated higher antibody responses after each vaccine dose than did people with HIV who were seronegative at baseline. High-level binding antibody cross-reactivity for the full-length spike and receptor-binding domain of the beta variant (B.1.351) was seen regardless of HIV status. In people with HIV who developed high titre responses, predominantly those who were receptor-binding domain seropositive at enrolment, neutralising activity against beta was retained.

Interpretation: ChAdOx1 nCoV-19 was well tolerated, showing favourable safety and immunogenicity in people with HIV, including heightened immunogenicity in SARS-CoV-2 baseline-seropositive participants. People with HIV showed cross-reactive binding antibodies to the beta variant and Asp614Gly wild-type, and high responders retained neutralisation against beta.

Funding: The Bill & Melinda Gates Foundation, South African Medical Research Council, UK Research and Innovation, UK National Institute for Health Research, and the South African Medical Research Council.
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http://dx.doi.org/10.1016/S2352-3018(21)00157-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372504PMC
September 2021

Two doses of SARS-CoV-2 vaccination induce robust immune responses to emerging SARS-CoV-2 variants of concern.

Nat Commun 2021 08 17;12(1):5061. Epub 2021 Aug 17.

School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, 4001, South Africa.

The extent to which immune responses to natural infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and immunization with vaccines protect against variants of concern (VOC) is of increasing importance. Accordingly, here we analyse antibodies and T cells of a recently vaccinated, UK cohort, alongside those recovering from natural infection in early 2020. We show that neutralization of the VOC compared to a reference isolate of the original circulating lineage, B, is reduced: more profoundly against B.1.351 than for B.1.1.7, and in responses to infection or a single dose of vaccine than to a second dose of vaccine. Importantly, high magnitude T cell responses are generated after two vaccine doses, with the majority of the T cell response directed against epitopes that are conserved between the prototype isolate B and the VOC. Vaccination is required to generate high potency immune responses to protect against these and other emergent variants.
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http://dx.doi.org/10.1038/s41467-021-25167-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371089PMC
August 2021

Protection by vaccination of children against typhoid fever with a Vi-tetanus toxoid conjugate vaccine in urban Bangladesh: a cluster-randomised trial.

Lancet 2021 08 9;398(10301):675-684. Epub 2021 Aug 9.

International Centre for Diarrhoeal Disease Research, Bangladesh, Dhaka, Bangladesh; University of California Los Angeles, Fielding School of Public Health, Los Angeles, CA, USA.

Background: Typhoid fever remains a major cause of morbidity and mortality in low-income and middle-income countries. Vi-tetanus toxoid conjugate vaccine (Vi-TT) is recommended by WHO for implementation in high-burden countries, but there is little evidence about its ability to protect against clinical typhoid in such settings.

Methods: We did a participant-masked and observer-masked cluster-randomised trial preceded by a safety pilot phase in an urban endemic setting in Dhaka, Bangladesh. 150 clusters, each with approximately 1350 residents, were randomly assigned (1:1) to either Vi-TT or SA 14-14-2 Japanese encephalitis (JE) vaccine. Children aged 9 months to less than 16 years were invited via parent or guardian to receive a single, parenteral dose of vaccine according to their cluster of residence. The study population was followed for an average of 17·1 months. Total and overall protection by Vi-TT against blood culture-confirmed typhoid were the primary endpoints assessed in the intention-to-treat population of vaccinees or all residents in the clusters. A subset of approximately 4800 participants was assessed with active surveillance for adverse events. The trial is registered at www.isrctn.com, ISRCTN11643110.

Findings: 41 344 children were vaccinated in April-May, 2018, with another 20 412 children vaccinated at catch-up vaccination campaigns between September and December, 2018, and April and May, 2019. The incidence of typhoid fever (cases per 100 000 person-years) was 635 in JE vaccinees and 96 in Vi-TT vaccinees (total Vi-TT protection 85%; 97·5% CI 76 to 91, p<0·0001). Total vaccine protection was consistent in different age groups, including children vaccinated at ages under 2 years (81%; 95% CI 39 to 94, p=0·0052). The incidence was 213 among all residents in the JE clusters and 93 in the Vi-TT clusters (overall Vi-TT protection 57%; 97·5% CI 43 to 68, p<0·0001). We did not observe significant indirect vaccine protection by Vi-TT (19%; 95% CI -12 to 41, p=0·20). The vaccines were well tolerated, and no serious adverse events judged to be vaccine-related were observed.

Interpretation: Vi-TT provided protection against typhoid fever to children vaccinated between 9 months and less than 16 years. Longer-term follow-up will be needed to assess the duration of protection and the need for booster doses.

Funding: The study was funded by the Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.1016/S0140-6736(21)01124-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387974PMC
August 2021

Prospects of future typhoid and paratyphoid vaccines in endemic countries.

J Infect Dis 2021 Aug 10. Epub 2021 Aug 10.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.

Low- and middle-income countries face a high burden of typhoid and paratyphoid fever due to poor water quality and inadequate sanitation. The World Health Organization (WHO) recommends the use of typhoid conjugate vaccines (TCV) in endemic settings and Gavi, the Vaccine Alliance, supports TCV introduction. There are currently two WHO-prequalified TCVs with Typbar TCV® introduced in Pakistan, Liberia, and Zimbabwe. Countries should assess disease burden and consider introduction of TCV for programmatic use. Several paratyphoid vaccine candidates are in early stages of development. An effective bivalent vaccine would be the most efficient way to control typhoid and paratyphoid fever.
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http://dx.doi.org/10.1093/infdis/jiab393DOI Listing
August 2021

Persistence of Immunity Following 2-Dose Priming with a 10-Valent Pneumococcal Conjugate Vaccine at 6 and 10 Weeks or 6 and 14 Weeks of Age in Nepalese Toddlers.

Pediatr Infect Dis J 2021 Oct;40(10):937-943

From the Paediatric Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.

Background: The pneumococcal conjugate vaccine has had a substantial impact on invasive pneumococcal disease. Previously, we compared immunity following vaccination with the 10-valent pneumococcal conjugate vaccine (PCV10) administered at 2 slightly different schedules: at 6 and 10 weeks of age, and at 6 and 14 weeks of age, both followed by a 9-month booster. In this study, we followed up those participants to evaluate the medium-term persistence of serotype-specific pneumococcal immunity at 2-3 years of age.

Method: Children from the previous studies were contacted and after taking informed consent from their parents, blood samples and nasopharyngeal swabs were collected. Serotype-specific IgG antibody concentrations were determined by enzyme-linked immunosorbent assay, for the 10 vaccine serotypes, at a WHO pneumococcal serology reference laboratory.

Findings: Two hundred twenty of the 287 children who completed the primary study returned at 2-3 years of age to provide a blood sample and nasopharyngeal swab. The nasopharyngeal carriage rate of PCV10 serotypes in the 6 + 14 group was higher than the 6 + 10 group (13.4% vs. 1.9%). Nevertheless, the proportion of toddlers with serum pneumococcal serotype-specific IgG greater than or equal to 0.35 µg/mL was comparable for all PCV10 serotypes between the 6 + 10 week and 6 + 14 week groups. Similarly, the geometric mean concentrations of serum pneumococcal serotype-specific IgG levels were similar in the 2 groups for all serotypes, except for serotype 19F which was 32% lower in the 6 + 10 group than the 6 + 14 group.

Conclusion: Immunization with PCV10 at 6 + 10 weeks or 6 + 14 weeks, with a booster at 9 months in each case, results in similar persistence of serotype-specific antibody at 2-3 years of age. Thus, protection from pneumococcal disease is expected to be similar when either schedule is used.
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http://dx.doi.org/10.1097/INF.0000000000003223DOI Listing
October 2021

ChAdOx1 nCoV-19 Vaccine Efficacy against the B.1.351 Variant. Reply.

N Engl J Med 2021 08 21;385(6):571-572. Epub 2021 Jul 21.

University of Oxford, Oxford, United Kingdom.

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http://dx.doi.org/10.1056/NEJMc2110093DOI Listing
August 2021

Should we delay covid-19 vaccination in children?

BMJ 2021 07 8;374:n1687. Epub 2021 Jul 8.

Department of Philosophy, University of Western Ontario, Canada

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http://dx.doi.org/10.1136/bmj.n1687DOI Listing
July 2021

Reduced neutralization of SARS-CoV-2 B.1.617 by vaccine and convalescent serum.

Cell 2021 08 17;184(16):4220-4236.e13. Epub 2021 Jun 17.

NIHR Oxford Biomedical Research Centre, Oxford, UK; Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has undergone progressive change, with variants conferring advantage rapidly becoming dominant lineages, e.g., B.1.617. With apparent increased transmissibility, variant B.1.617.2 has contributed to the current wave of infection ravaging the Indian subcontinent and has been designated a variant of concern in the United Kingdom. Here we study the ability of monoclonal antibodies and convalescent and vaccine sera to neutralize B.1.617.1 and B.1.617.2, complement this with structural analyses of Fab/receptor binding domain (RBD) complexes, and map the antigenic space of current variants. Neutralization of both viruses is reduced compared with ancestral Wuhan-related strains, but there is no evidence of widespread antibody escape as seen with B.1.351. However, B.1.351 and P.1 sera showed markedly more reduction in neutralization of B.1.617.2, suggesting that individuals infected previously by these variants may be more susceptible to reinfection by B.1.617.2. This observation provides important new insights for immunization policy with future variant vaccines in non-immune populations.
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http://dx.doi.org/10.1016/j.cell.2021.06.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218332PMC
August 2021

Should we be vaccinating children against COVID-19 in high-income countries?

Expert Rev Vaccines 2021 09 19;20(9):1043-1046. Epub 2021 Jul 19.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Centre for Clinical Vaccinology and Tropical Medicine (CCVTM), Oxford, UK.

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http://dx.doi.org/10.1080/14760584.2021.1951245DOI Listing
September 2021

A Typhi Controlled Human Infection Study for Assessing Correlation between Bactericidal Antibodies and Protection against Infection Induced by Typhoid Vaccination.

Microorganisms 2021 Jun 28;9(7). Epub 2021 Jun 28.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the NIHR Oxford Biomedical Research Centre, Oxford OX3 9DU, UK.

Vi-polysaccharide conjugate vaccines are efficacious against typhoid fever in children living in endemic settings, their recent deployment is a promising step in the control of typhoid fever. However, there is currently no accepted correlate of protection. IgG and IgA antibodies generated in response to Vi conjugate or Vi plain polysaccharide vaccination are important but there are no definitive protective titre thresholds. We adapted a luminescence-based serum bactericidal activity (SBA) for use with Typhi and assessed whether bactericidal antibodies induced by either Vi tetanus toxoid conjugate (Vi-TT) or Vi plain polysaccharide (Vi-PS) were associated with protection in a controlled human infection model of typhoid fever. Both Vi-PS and Vi-TT induced significant increase in SBA titre after 28 days (Vi-PS; < 0.0001, Vi-TT; = 0.003), however higher SBA titre at the point of challenge did not correlate with protection from infection or reduced symptom severity. We cannot eliminate the role of SBA as part of a multifactorial immune response which protects against infection, however, our results do not support a strong role for SBA as a mechanism of Vi vaccine mediated protection in the CHIM setting.
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http://dx.doi.org/10.3390/microorganisms9071394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304662PMC
June 2021

T-cell mediated immunity after AZD1222 vaccination: A polyfunctional spike-specific Th1 response with a diverse TCR repertoire.

medRxiv 2021 Jul 13. Epub 2021 Jul 13.

AZD1222 (ChAdOx1 nCoV-19), a replication-deficient simian adenovirus-vectored vaccine, has demonstrated safety, efficacy, and immunogenicity against coronavirus disease 2019 (COVID-19) in clinical trials and real-world studies. We characterized CD4+ and CD8+ T-cell responses induced by AZD1222 vaccination in peripheral blood mononuclear cells (PBMCs) from 280 unique vaccine recipients aged 18-85 years who enrolled in the phase 2/3 COV002 trial. Total spike-specific CD4+ T cell helper type 1 (Th1) and CD8+ T-cell responses were significantly increased in AZD1222-vaccinated adults of all ages following two doses of AZD1222. CD4+ Th2 responses following AZD1222 vaccination were not detected. Furthermore, AZD1222-specific Th1 and CD8+ T cells both displayed a high degree of polyfunctionality in all adult age groups. T-cell receptor (TCR) β sequences from vaccinated participants mapped against TCR sequences known to react to SARS-CoV-2 revealed substantial breadth and depth across the SARS-CoV-2 spike protein for the AZD1222-induced CD4+ and CD8+ T-cell responses. Overall, AZD1222 vaccination induced a robust, polyfunctional Th1-dominated T-cell response, with broad CD4+ and CD8+ T-cell coverage across the SARS-CoV-2 spike protein.

One Sentence Summary: Polyfunctional CD4+ and CD8+ T-cell responses are elicited against the SARS-CoV-2 spike protein following vaccination with AZD1222.
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http://dx.doi.org/10.1101/2021.06.17.21259027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240693PMC
July 2021

Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 in HIV infection: a single-arm substudy of a phase 2/3 clinical trial.

Lancet HIV 2021 08 18;8(8):e474-e485. Epub 2021 Jun 18.

Nuffield Department of Clinical Medicine and Oxford Vaccine Group, University of Oxford, Oxford, UK.

Background: Data on vaccine immunogenicity against SARS-CoV-2 are needed for the 40 million people globally living with HIV who might have less functional immunity and more associated comorbidities than the general population. We aimed to explore safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine in people with HIV.

Methods: In this single-arm open-label vaccination substudy within the protocol of the larger phase 2/3 trial COV002, adults aged 18-55 years with HIV were enrolled at two HIV clinics in London, UK. Eligible participants were required to be on antiretroviral therapy (ART), with undetectable plasma HIV viral loads (<50 copies per mL), and CD4 counts of more than 350 cells per μL. A prime-boost regimen of ChAdOx1 nCoV-19, with two doses was given 4-6 weeks apart. The primary outcomes for this substudy were safety and reactogenicity of the vaccine, as determined by serious adverse events and solicited local and systemic reactions. Humoral responses were measured by anti-spike IgG ELISA and antibody-mediated live virus neutralisation. Cell-mediated immune responses were measured by ex-vivo IFN-γ enzyme-linked immunospot assay (ELISpot) and T-cell proliferation. All outcomes were compared with an HIV-uninfected group from the main COV002 study within the same age group and dosing strategy and are reported until day 56 after prime vaccination. Outcomes were analysed in all participants who received both doses and with available samples. The COV002 study is registered with ClinicalTrials.gov, NCT04400838, and is ongoing.

Findings: Between Nov 5 and Nov 24, 2020, 54 participants with HIV (all male, median age 42·5 years [IQR 37·2-49·8]) were enrolled and received two doses of ChAdOx1 nCoV-19. Median CD4 count at enrolment was 694·0 cells per μL (IQR 573·5-859·5). No serious adverse events occurred. Local and systemic reactions occurring during the first 7 days after prime vaccination included pain at the injection site (26 [49%] of 53 participants with available data), fatigue (25 [47%]), headache (25 [47%]), malaise (18 [34%]), chills (12 [23%]), muscle ache (19 [36%]), joint pain (five [9%]), and nausea (four [8%]), the frequencies of which were similar to the HIV-negative participants. Anti-spike IgG responses by ELISA peaked at day 42 (median 1440 ELISA units [EUs; IQR 704-2728]; n=50) and were sustained until day 56 (median 941 EUs [531-1445]; n=49). We found no correlation between the magnitude of the anti-spike IgG response at day 56 and CD4 cell count (p=0·93) or age (p=0·48). ELISpot and T-cell proliferative responses peaked at day 14 and 28 after prime dose and were sustained to day 56. Compared with participants without HIV, we found no difference in magnitude or persistence of SARS-CoV-2 spike-specific humoral or cellular responses (p>0·05 for all analyses).

Interpretation: In this study of people with HIV, ChAdOx1 nCoV-19 was safe and immunogenic, supporting vaccination for those well controlled on ART.

Funding: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.
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http://dx.doi.org/10.1016/S2352-3018(21)00103-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213361PMC
August 2021

ChAdOx1 nCoV-19 vaccine: asymptomatic efficacy estimates - Authors' reply.

Lancet 2021 06;397(10291):2248

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford OX3 7LE, UK. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(21)00976-4DOI Listing
June 2021

Injection fears and COVID-19 vaccine hesitancy.

Psychol Med 2021 Jun 11:1-11. Epub 2021 Jun 11.

The Psychometrics Centre, University of Cambridge, Cambridge, UK.

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.
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http://dx.doi.org/10.1017/S0033291721002609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220023PMC
June 2021

Systems Immunology: Revealing Influenza Immunological Imprint.

Viruses 2021 05 20;13(5). Epub 2021 May 20.

Institute of Immunity, Transplantation and Infection, School of Medicine, Stanford University, Stanford, CA 94304, USA.

Understanding protective influenza immunity and identifying immune correlates of protection poses a major challenge and requires an appreciation of the immune system in all of its complexity. While adaptive immune responses such as neutralizing antibodies and influenza-specific T lymphocytes are contributing to the control of influenza virus, key factors of long-term protection are not well defined. Using systems immunology, an approach that combines experimental and computational methods, we can capture the systems-level state of protective immunity and reveal the essential pathways that are involved. New approaches and technological developments in systems immunology offer an opportunity to examine roles and interrelationships of clinical, biological, and genetic factors in the control of influenza infection and have the potential to lead to novel discoveries about influenza immunity that are essential for the development of more effective vaccines to prevent future pandemics. Here, we review recent developments in systems immunology that help to reveal key factors mediating protective immunity.
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http://dx.doi.org/10.3390/v13050948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160800PMC
May 2021
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