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Background: AZD2816 is a variant-adapted COVID-19 vaccine that expresses the full-length SARS-CoV-2 beta variant spike protein but is otherwise similar to AZD1222 (ChAdOx1 nCoV-19). This study aimed to evaluate the safety and immunogenicity of AZD1222 or AZD2816 (or both) primary-series vaccination in a cohort of adult participants who were previously unvaccinated., Methods: In this phase 2/3, randomised, multinational, active-controlled, non-inferiority, immunobridging study, adult participants previously unvaccinated for COVID-19 were enrolled at 16 study sites in Brazil, South Africa, Poland, and the UK. Participants were stratified by age, sex, and comorbidity and randomly assigned 5:5:5:2 to receive a primary series of AZD1222 (AZD1222 group), AZD2816 (AZD2816 [4-week] group), or AZD1222-AZD2816 (AZD1222-AZD2816 group) at 4-week dosing intervals, or AZD2816 at a 12-week interval (AZD2816 [12-week] group) and evaluated for safety and immunogenicity through 180 days after dose 2. Primary outcomes were safety (rates of solicited adverse events occurring during 7 days and unsolicited adverse events occurring during 28 days after each dose) and immunogenicity (non-inferiority of pseudovirus neutralising antibody geometric mean titre [GMT], GMT ratio margin of 0·67, and seroresponse rate, rate difference margin of -10%, recorded 28 days after dose 2 with AZD2816 [4-week interval] against beta vs AZD1222 against ancestral SARS-CoV-2) in participants who were seronegative at baseline. This trial is registered with ClinicalTrials.gov, NCT04973449, and is completed., Findings: Between July 7 and Nov 12, 2021, 1449 participants were assigned to the AZD1222 group (n=413), the AZD2816 (4-week) group (n=415), the AZD1222-AZD2816 group (n=412), and the AZD2816 (12-week) group (n=209). Ten (2·6%) of 378 participants who were seronegative at baseline in the AZD1222 group, nine (2·4%) of 379 in the AZD2816 (4-week) group, eight (2·1%) of 380 in the AZD1222-AZD2816 group, and 11 (5·8%) of 191 in the AZD2816 (12-week) group had vaccine-related unsolicited adverse events. Serious adverse events were recorded in one (0·3%) participant in the AZD1222 group, one (0·3%) in the AZD2816 (4-week) group, two (0·5%) in the AZD1222-AZD2816 group, and none in the AZD2816 (12-week) group. Co-primary immunogenicity endpoints were met: neutralising antibody GMT (ratio 1·19 [95% CI 1·08-1·32]; lower bound greater than 0·67) and seroresponse rate (difference 1·7% [-3·1 to 6·5]; lower bound greater than -10%) at 28 days after dose 2 were non-inferior in the AZD2816 (4-week) group against beta versus in the AZD1222 group against ancestral SARS-CoV-2. Seroresponse rates were highest with AZD2816 against beta (12-week interval 94·3% [95% CI 89·4-97·3]; 4-week interval 85·7% [81·5-89·2]) and with AZD1222 (84·6% [80·3-88·2]) against ancestral SARS-CoV-2., Interpretation: Primary series of AZD1222 and AZD2816 were well tolerated, with no emergent safety concerns. Both vaccines elicited robust immunogenicity against beta and ancestral SARS-CoV-2 with greater responses demonstrated when testing against SARS-CoV-2 strains that matched those targeted by the respective vaccine. These findings demonstrate the continued importance of ancestral COVID-19 vaccines in protecting against severe COVID-19 and highlight the feasibility of using the ChAdOx1 platform to develop COVID-19 vaccines against future SARS-CoV-2 variants., Funding: AstraZeneca., Competing Interests: Declaration of interests SACC declares participation in the clinical development, with University of Oxford, of the vaccines described in this Article, membership on CureVac and Clover advisory boards, and institutional research grants from AstraZeneca. BJ is an employee of Cytel and is currently on assignment to AstraZeneca. QEB declares institutional funding, the provision of study materials, or both from the Wits Health Consortium, the Bill & Melinda Gates Foundation, the South African Medical Research Council, and AstraZeneca, as well as research grants or contracts from Regeneron, Novo Nordisk, Avillion, GlaxoSmithKline, Novavax, Sinovac, Johnson & Johnson, and Pfizer pharmaceuticals. PKA declares institutional grants to support the conduct of the study from AstraZeneca and the UK Vaccine Taskforce via the UK National Institute for Health Research (NIHR). HB is an employee of Bogier consulting and is currently on assignment to AstraZeneca. EJK is an employee of Sanofi. SM is an employee of Exploristics and is currently on assignment to AstraZeneca. EPM declares no competing interests. TL declares consulting fees from Vaccitech on an unrelated project, an honorarium from Seqirus on an unrelated project, an institutional grant from the UK Vaccine Taskforce via the NIHR, work-related investments, and is a named inventor on a patent application for a vaccine against SARS-CoV-2. JJL declares no competing interests. MNR declares institutional support for the study from AstraZeneca. AJP is Chair of the UK Department of Health and Social Care’s Joint Committee on Vaccination and Immunisation (JCVI) but does not participate in the JCVI COVID-19 committee. AJP also declares membership of the WHO’s Strategic Advisory Group of Experts on Immunization until January, 2022; provision of advice to Shionogi on COVID-19; and funding from the NIHR, AstraZeneca, the Bill & Melinda Gates Foundation, Wellcome, the UK Research and Innovation Medical Research Council, the Serum Institute of India, and the Coalition for Epidemic Preparedness Innovations. University of Oxford has entered a partnership with AstraZeneca for the development of COVID-19 vaccines; TL, MNR, SB, PKA, and AJP are contributors to the intellectual property licensed by Oxford University Innovation to AstraZeneca. AA, TA, EJK, MK, UO, SS, KS, AS, TV, and JAG are, or were, employees of and may hold (or have held) stock or stock options in AstraZeneca. MSMdOP declares no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: The currently licensed quadrivalent MenACWY-CRM conjugate vaccine presentation consists of two vials (lyophilized MenA and liquid MenCWY) to be reconstituted before injection. A new fully liquid, single-vial formulation has been developed to simplify administration and prevent reconstitution errors. We present pooled safety data from two randomized, controlled, observer-blind phase 2b clinical trials, in which the fully liquid presentation was compared with the licensed presentation., Methods: This is a post hoc analysis of two studies, in which safety data from participants aged 10-40 years who received one dose of either liquid MenACWY-CRM (1337 participants; MenACWY liquid group) or licensed MenACWY-CRM (1332 participants; MenACWY licensed group) were pooled. Frequencies were calculated for solicited adverse events (AEs) during 7 days post-vaccination and unsolicited AEs, including medically attended AEs and serious AEs (SAEs), during the 6-month safety follow-up period. Analysis results are presented by vaccine group, overall and by age category (10-17 and 18-40 years)., Results: Overall, AEs solicited for collection during the first 7 days after vaccination were reported by similar percentages of participants (69.2%, MenACWY liquid; 68.2%, MenACWY licensed), and were generally mild/moderate in intensity. Solicited local AEs were reported by 46.0% of the MenACWY liquid group and 43.5% of the MenACWY licensed group and solicited systemic AEs by 55.2 and 54.1%, respectively. During the 6-month post-vaccination period, unsolicited AEs were reported by 32.2 and 31.2% of the MenACWY liquid group and MenACWY licensed group, respectively, and medically attended AEs by 18.6 and 17.3%, respectively. Overall, 14 participants in each group (1.0 and 1.1%, respectively) reported SAEs, none of which was considered vaccine-related by the investigator. The safety profiles of both MenACWY-CRM presentations were similar for each age group and overall., Conclusions: This pooled analysis shows the safety profile of fully liquid MenACWY-CRM is comparable with that of the currently licensed vaccine presentation., Clinical Trial Registration: ClinicalTrials.gov Identifiers: NCT03652610 (August 29, 2018), NCT03433482 (14 February 2018)., (© 2022. GSK.)

A fully liquid MenACWY-CRM vaccine presentation has been developed, modifying the meningococcal serogroup A (MenA) component from lyophilized to liquid. The safety and immunogenicity of the liquid presentation at the end of the intended shelf-life (aged for 24 or 30 months) were compared to the licensed lyophilized/liquid presentation. This multicenter, randomized (1:1), observer-blind, phase 2b study (NCT03433482) enrolled adolescents and young adults (age 10-40 years). In part 1, 844 participants received one dose of liquid presentation stored for approximately 24 months or licensed presentation. In part 2, 846 participants received one dose of liquid presentation stored for approximately 30 months or licensed presentation. After storage, the MenA free saccharide (FS) level was approximately 25% and O-acetylation was approximately 45%. The primary objective was to demonstrate non-inferiority of the liquid presentation to licensed presentation, as measured by human serum bactericidal assay (hSBA) geometric mean titers (GMTs) against MenA, 1-month post-vaccination. Immune responses against each vaccine serogroup were similar between groups. Between-group ratios of hSBA GMTs for MenA were 1.21 (part 1) and 1.11 (part 2), with two-sided 95% confidence interval lower limits (0.94 and 0.87, respectively) greater than the prespecified non-inferiority margin (0.5), thus meeting the primary study objective. No safety concerns were identified. Despite reduced O-acetylation of MenA and increased FS content, serogroup-specific immune responses induced by the fully liquid presentation were similar to those induced by the licensed MenACWY-CRM vaccine, with non-inferior anti-MenA responses. The safety profiles of the vaccine presentations were similar.

Background: The currently licensed quadrivalent MenACWY-CRM conjugate vaccine presentation consists of two vials (lyophilised MenA and liquid MenCWY) to be reconstituted before injection. A new fully liquid formulation in a single vial has been developed to further improve the vaccine presentation. Since the MenA structure is subject to hydrolytic degradation, this study was conducted to compare the immunogenicity and safety of the investigational MenACWY-CRM liquid vaccine with the licensed vaccine., Methods: In this multicentre, randomised, controlled, observer-blind, phase 2b study, 979 healthy adults were administered a single dose of MenACWY-CRM liquid presentation or the currently licensed MenACWY-CRM vaccine. MenA free saccharide generation was accelerated to approximately 30% in the liquid presentation and MenA polysaccharide O-acetylation was reduced to approximately 40%, according to a controlled procedure. Immunological non-inferiority of the MenACWY-CRM liquid to the licensed vaccine, as measured by human serum bactericidal assay (hSBA) geometric mean titres (GMTs) against MenA 1 month post-vaccination, was the primary study objective. Safety assessment was among the secondary objectives., Results: Immune responses against each serogroup were similar between the two vaccine groups and was non-inferior for MenA. Adjusted hSBA GMTs for MenA were 185.16 and 211.33 for the MenACWY-CRM liquid presentation and currently licensed vaccine presentation, respectively. The between-group ratio of hSBA GMTs for MenA was 0.88, with a two-sided 95% confidence interval lower limit of 0.64, greater than the prespecified non-inferiority margin of 0.5, thus meeting the primary study objective. Both vaccines were well tolerated. No serious adverse events were considered related to vaccination., Conclusions: The levels of MenA free saccharide and polysaccharide O-acetylation did not affect the immunogenicity of the fully liquid presentation, which was demonstrated to be non-inferior to the immunogenicity of the currently licensed MenACWY-CRM vaccine against MenA. The immunogenicity, reactogenicity and safety profiles of the two vaccine presentations were similar., Competing Interests: Declaration of Competing Interest TA, SVH, MA, BK, BdW, GFDD, MC, PVS, EF, ML and MP are employed by the GSK group of companies. TA, MA, BdW, PVS, EF, ML and MP hold shares in the GSK group of companies. CV reports her institution received payments from the GSK group of companies, MSD and Pfizer, outside the submitted work. ILR reports her institution received payments from the GSK group of companies for the conduct of the study. TN reports payments from the GSK group of companies, Merck, Sanofi Pasteur and Seqirus, outside the submitted work. TA, SVH, MA, BK, BdW, GFDD, MC, PVS, EF, ML, MP, CV, ILR and TN declare no other financial and non-financial relationships and activities. JV, TS, GG, MF, GI, TFS, AMN and SC declare no financial and non-financial relationships and activities and no conflicts of interest., (Copyright © 2021 GlaxoSmithKline Biologicals S.A. Published by Elsevier Ltd.. All rights reserved.)

Environmental Enteric Dysfunction (EED) is an acquired small intestinal inflammatory condition underlying high rates of stunting in children <5 years of age in low- and middle-income countries. Children with EED are known to have repeated exposures to enteropathogens and environmental toxins that leads to malabsorptive syndrome. We aimed to characterize association of linear growth faltering with enteropathogen burden and subsequent changes in EED biomarkers. In a longitudinal birth cohort (n = 272), monthly anthropometric measurements (Length for Age Z score- LAZ) of asymptomatic children were obtained up to 18 months. Biological samples were collected at 6 and 9 months for the assessment of biomarkers. A customized TaqMan array card was used to target 40 enteropathogens in fecal samples. Linear regression was applied to study the effect of specific enteropathogen infection on change in linear growth (ΔLAZ). Presence of any pathogen in fecal sample correlated with serum flagellin IgA (6 mo, r = 0.19, p = 0.002), fecal Reg 1b (6 mo, r = 0.16, p = 0.01; 9mo, r = 0.16, p = 0.008) and serum Reg 1b (6 mo, r = 0.26, p<0.0001; 9 mo, r = 0.15, p = 0.008). At 6 months, presence of Campylobacter [β (SE) 7751.2 (2608.5), p = 0.003] and ETEC LT [β (SE) 7089.2 (3015.04), p = 0.019] was associated with increase in MPO. Giardia was associated with increase in Reg1b [β (SE) 72.189 (26.394), p = 0.006] and anti-flic IgA[β (SE) 0.054 (0.021), p = 0.0091]. Multiple enteropathogen infections in early life negatively correlated with ΔLAZ, and simultaneous changes in gut inflammatory and permeability markers. A combination vaccine targeting enteropathogens in early life could help in the prevention of future stunting., Competing Interests: The authors have declared that no competing interests exist.

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Background: Benefits of pneumococcal conjugate vaccine programs have been linked to the vaccine's ability to disrupt nasopharyngeal carriage and transmission. The 10-valent pneumococcal vaccine (PCV10) was included in the Expanded Program on Immunization (EPI) in Sindh, Pakistan in February 2013. This study was carried out immediately before PCV10 introduction to establish baseline pneumococcal carriage and prevalent serotypes in young children and to determine if carriage differed in urban and rural communities., Methods: Nasopharyngeal specimens were collected from a random sample of children 3-11 and 12-59 months of age in an urban community (Karachi) and children 3-11 months of age in a rural community (Matiari). Samples were processed in a research laboratory in Karachi. Samples were transported in STGG media, enriched in Todd Hewitt broth, rabbit serum and yeast extract, cultured on 5% sheep blood agar, and serotyped using the CDC standardized sequential multiplex PCR assay. Serotypes were categorized into PCV10-type and non-vaccine types., Results: We enrolled 670 children. Pneumococci were detected in 73.6% and 79.5 % of children in the infant group in Karachi and Matiari, respectively, and 78.2% of children 12 to 59 months of age in Karachi. In infants, 38.9% and 33.5% of those carrying pneumococci in Karachi and Matiari, respectively, had PCV10 types. In the older age group in Karachi, the proportion was 30.7%, not significantly different from infants. The most common serotypes were 6A, 23F, 19A, 6B and 19F., Conclusion: We found that about 3 of 4 children carried pneumococci, and this figure did not vary with age group or urban or rural residence. Planned annual surveys in the same communities will inform change in carriage of PCV10 serotype pneumococci after the introduction and uptake of PCV10 in these communities.

Background: Environmental Enteric Dysfunction (EED) in children from low-income countries has been linked to linear growth declines. There is a critical need to identify sensitive and early EED biomarkers., Objective: Determine whether levels of antibodies against bacterial components flagellin (flic) and lipopolysaccharide (LPS) predict poor growth., Design/methods: In a prospective birth cohort of 380 children in rural Pakistan blood and stool samples were obtained at ages 6 and 9 months. Linear mixed effects models were used to examine longitudinal associations between quartiles of anti-flic and anti-LPS antibodies and changes in LAZ, WAZ and WLZ scores. Spearman's correlations were measured between anti-flic and anti-LPS immunoglobulins with measures of systemic/enteric inflammation and intestinal regeneration., Results: Anti-LPS IgA correlated significantly with CRP, AGP and Reg1 serum at 6mo and with MPO at 9mo. In multivariate analysis at 6mo of age, higher anti-LPS IgA levels predicted greater declines in LAZ scores over subsequent 18mo (comparing highest to lowest quartile, β (SE) change in LAZ score/year = -0.313 (0.125), p-value = 0.013). Anti-flic Ig A in the two highest quartiles measured at 9mo of age had declines in LAZ of -0.269 (0.126), p = 0.033; and -0.306 (0.129), p = 0.018 respectively, during the subsequent 18mo of life, compared to those in the lowest quartile of anti-flic IgA., Conclusions and Relevance: Elevated anti-flic IgA and anti-LPS IgA antibodies at 6 and 9mo, predict declines in linear growth. Systemic and enteric inflammation correlated with anti-LPS IgA provides mechanistic considerations for potential future interventions.

Environmental Enteric Dysfunction (EED), a syndrome characterized by chronic gut inflammation, contributes towards stunting and poor response to enteric vaccines in children in developing countries. In this study, we evaluated major putative biomarkers of EED using growth faltering as its clinical proxy. Newborns (n = 380) were enrolled and followed till 18 months with monthly anthropometry. Biomarkers associated with gut and systemic inflammation were assessed at 6 and 9 months. Linear mixed effects model was used to determine the associations of these biomarkers with growth faltering between birth and 18 months. Fecal myeloperoxidase (neutrophil activation marker) at 6 months [β = -0.207, p = 0.005], and serum GLP 2 (enterocyte proliferation marker) at 6 and 9 months [6M: β = -0.271, p = 0.035; 9M: β = -0.267, p = 0.045] were associated with decreasing LAZ score. Ferritin at 6 and 9 months was associated with decreasing LAZ score [6M: β = -0.882, p < 0.0001; 9M: β = -0.714, p < 0.0001] and so was CRP [β = -0.451, p = 0.039] and AGP [β = -0.443, p = 0.012] at 9 months. Both gut specific and systemic biomarkers correlated negatively with IGF-1, but only weakly correlated, if at all with each other. We therefore conclude that EED may be contributing directly towards growth faltering, and this pathway is not entirely through the pathway of systemic inflammation.

The objective of this study was to determine the incidence of respiratory viruses associated with severe pneumonia among children less than 2 years of age in the rural district of Matiari in Sindh, Pakistan. This study was a community-based prospective cohort active surveillance of infants enrolled at birth and followed for 2 years. Cases were identified using the World Health Organization's Integrated Management of Childhood Illnesses' definition of severe pneumonia. Nasopharyngeal swabs were obtained for assessment by multiplex RT-PCR for eight viruses and their subtypes, including RSV, influenza virus, human metapneumovirus, enterovirus/rhinovirus, coronavirus, parainfluenza virus, adenovirus, and human bocavirus. Blood cultures were collected from febrile participants. A total of 817 newborns were enrolled and followed with fortnightly surveillance for 2 years, accounting for a total of 1,501 child-years of follow-up. Of the nasopharyngeal swabs collected, 77.8% (179/230) were positive for one or more of the above mentioned respiratory viruses. The incidence of laboratory confirmed viral-associated pneumonia was 11.9 per 100 child-years of follow-up. Enterovirus/rhinovirus was detected in 51.7% patients, followed by parainfluenza virus type III (8.3%), and RSV (5.7%). Of the uncontaminated blood cultures, 1.4% (5/356) were positive. Respiratory viruses are frequently detected during acute respiratory infection episodes in children under 2 years old in a rural community in Pakistan. However, causal association is yet to be established and the concomitant role of bacteria as a co-infection or super-infection needs further investigation. J. Med. Virol. 88:1882-1890, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: Powders containing iron and other micronutrients are recommended as a strategy to prevent nutritional anaemia and other micronutrient deficiencies in children. We assessed the effects of provision of two micronutrient powder formulations, with or without zinc, to children in Pakistan., Methods: We did a cluster randomised trial in urban and rural sites in Sindh, Pakistan. A baseline survey identified 256 clusters, which were randomly assigned (within urban and rural strata, by computer-generated random numbers) to one of three groups: non-supplemented control (group A), micronutrient powder without zinc (group B), or micronutrient powder with 10 mg zinc (group C). Children in the clusters aged 6 months were eligible for inclusion in the study. Powders were to be given daily between 6 and 18 months of age; follow-up was to age 2 years. Micronutrient powder sachets for groups B and C were identical except for colour; investigators and field and supervisory staff were masked to composition of the micronutrient powders until trial completion. Parents knew whether their child was receiving supplementation, but did not know whether the powder contained zinc. Primary outcomes were growth, episodes of diarrhoea, acute lower respiratory tract infection, fever, and incidence of admission to hospital. This trial is registered with ClinicalTrials.gov, number NCT00705445., Results: The trial was done between Nov 1, 2008, and Dec 31, 2011. 947 children were enrolled in group A clusters, 910 in group B clusters, and 889 in group C clusters. Micronutrient powder administration was associated with lower risk of iron-deficiency anaemia at 18 months compared with the control group (odds ratio [OR] for micronutrient powder without zinc=0·20, 95% CI 0·11-0·36; OR for micronutrient powder with zinc=0·25, 95% CI 0·14-0·44). Compared with the control group, children in the group receiving micronutrient powder without zinc gained an extra 0·31 cm (95% CI 0·03-0·59) between 6 and 18 months of age and children receiving micronutrient powder with zinc an extra 0·56 cm (0·29-0·84). We recorded strong evidence of an increased proportion of days with diarrhoea (p=0·001) and increased incidence of bloody diarrhoea (p=0·003) between 6 and 18 months in the two micronutrient powder groups, and reported chest indrawing (p=0·03). Incidence of febrile episodes or admission to hospital for diarrhoea, respiratory problems, or febrile episodes did not differ between the three groups., Interpretation: Use of micronutrient powders reduces iron-deficiency anaemia in young children. However, the excess burden of diarrhoea and respiratory morbidities associated with micronutrient powder use and the very small effect on growth recorded suggest that a careful assessment of risks and benefits must be done in populations with malnourished children and high diarrhoea burdens., Funding: Bill & Melinda Gates Foundation., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Nosocomial infection is defined as an infection which develops 48 hours after hospital admission or within 48 hours after being discharged. The objectives were to assess the frequency of nosocomial infection in patients admitted to intensive care unit (ICU) and to determine the etiological factors in such patients. It was an Observational Study and conducted in Intensive Care Unit, Liaquat University Hospital Hyderabad Sindh Pakistan from January 2008 to November 2008., Methods: All patients above 16 years of age admitted in the ICU for more than 48 hours and developed clinical evidence of infection that did not originate from patients' original diagnosis at the time of admission, were included in the study. Data was entered in a proforma and analyzed using SPSS version 10.0., Results: During the study period, 97 out of 333 patients acquired nosocomial infection. The frequency of nosocomial infection was 29.13%. Respiratory tract infection was seen in 29 (30.1%), urinary tract infection in 38 (39.1%) and blood stream infection in 23 (23.7%) patients. Other infections we identified were skin, soft tissue, wound and gastrointestinal tract infections., Conclusion: Patients admitted in intensive care unit are at more risk of acquiring nosocomial infection from different sources. It is suggested that proper nursing care, sterilization and disinfection of instruments and equipment and careful handling of invasive procedures are the best tool to control these life threatening infections.