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Lassa fever is a serious epidemic viral disease in West Africa affecting an estimated 2 million people annually with about 5000-10,000 deaths, although supporting data is sparse. Lassa fever significantly affects neonates, children, and pregnant women, however, comprehensive data on its impact in these populations are lacking. We reviewed the available literature on Lassa fever to assess its prevalence and impact in these populations and implications for vaccine development. Clinical features in children were similar to those observed in adults, with complications such as bleeding. Altered mental status, anasarca (swollen baby syndrome), bleeding, and poor urine output were risk factors for death. The case fatality rate (CFR) in 16 paediatric studies ranged from 6 % to 63 % and was 66.7 % and 75.0 % in two neonatal studies. In a systematic review of studies on pregnant women the CFR was 33.73 %. The adverse foetal outcomes included miscarriage, stillbirth, and intrauterine death associated with maternal death. Since Lassa fever significantly affects neonates, children, and pregnant women, developing a safe and effective, single-dose vaccine for these high-risk populations is vital. Currently, there are four clinical trials assessing Lassa virus vaccines. Only one of these trials is enrolling children aged ≥18 months, and exclude pregnant and breast-feeding women. It is essential that pregnant and breast-feeding women and young children are included in clinical trials that incorporate robust safety surveillance and risk mitigation measures. In our review, potential approaches to address the specific gaps in the areas of diagnosis, management, and prevention of Lassa fever in these specific populations, such as disease surveillance systems and vaccine development, were identified. A comprehensive strategy with investment focused on addressing specific knowledge gaps will be essential in protecting the health of these specific populations in Lassa virus endemic regions., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Flor M Munoz reports financial support, administrative support, article publishing charges, and writing assistance were provided by Coalition for Epidemic Preparedness Innovations. Clare L Cutland reports a relationship with Pfizer that includes: funding grants. Clare L Cutland reports a relationship with BMGF that includes: funding grants. Clare L Cutland reports a relationship with GIZ that includes: funding grants. Flor M. Munoz is an associate editor for Vaccine. Helen Marshall declared being an investigator on vaccine clinical trials with institutional funding by pharmaceutic industry with no personal payments If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Background epidemiologic population data from low- and middle-income countries (LMIC), on maternal, foetal and neonatal adverse outcomes are limited. We aimed to estimate the incidence of maternal, foetal and neonatal adverse outcomes at South African maternal vaccine trial sites as reported directly in the clinical notes as well as using the 'Global Alignment of Immunization Safety Assessment in Pregnancy' case definitions (GAIA-CDs). GAIA-CDs were utilized as a tool to standardise data collection and outcome assessment, and the applicability and utility of the GAIA-CDs was evaluated in a LMIC observational study., Methods: We conducted a retrospective record review of maternity and neonatal case records for births that occurred in Soweto, Inner City- Johannesburg and Metro-East Cape Town, South Africa, between 1st July 2017 and 30th June 2018. Study staff abstracted data from randomly selected medical charts onto standardized study-specific forms. Incidence (per 100,000 population) was calculated for adverse maternal, foetal and neonatal outcomes, which were identified as priority outcomes in vaccine safety studies by the Brighton Collaboration and World Health Organization. Outcomes reported directly in the clinical notes and outcomes which fulfilled GAIA-CDs were compared. Incidence of outcomes was calculated by combining cases which were either reported in clinical notes by attending physicians and/ or fulfilled GAIA-CDs., Findings: Of 9371 pregnant women enrolled, 27·6% were HIV-infected, 19·9% attended antenatal clinic in the 1st trimester of pregnancy and 55·3% had ≥1 ultrasound examination. Fourteen percent of women had hypertensive disease of pregnancy, 1·3% had gestational diabetes mellitus and 16% experienced preterm labour. There were 150 stillbirths (1·6%), 26·8% of infants were preterm and five percent had microcephaly. Data available in clinical notes for some adverse outcomes, including maternal- & neonatal death, severe pre-eclampsia/ eclampsia, were able to fulfil GAIA-CDs criteria for all of the clinically-reported cases, however, missing data required to fulfil other GAIA-CD criteria (including stillbirth, gestational diabetes mellitus and gestational hypertension) led to poor correlation between clinically-reported adverse outcomes and outcomes fulfilling GAIA-CDs. Challenges were also encountered in accurately ascertaining gestational age., Interpretation: This study contributes to the expanding body of data on background rates of adverse maternal and foetal/ neonatal outcomes in LMICs. Utilization of GAIA-CDs assists with alignment of data, however, some GAIA-CDs require amendment to improve the applicability in LMICs., Funding: This study was funded by Pfizer (Inc)., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Clare L. Cutland reports financial support was provided by Pfizer Inc. Clare L. Cutland reports a relationship with Wits Health Consortium Pty Ltd that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: The GAIA (Global Alignment on Immunisation Safety Assessment in Pregnancy) consortium was established in 2014 with the aim of creating a standardised, globally coordinated approach to monitoring the safety of vaccines administered in pregnancy. The consortium developed twenty-six standardised definitions for classifying obstetric and infant adverse events. This systematic review sought to evaluate the current state of adverse event reporting in maternal vaccine trials following the publication of the case definitions by GAIA, and the extent to which these case definitions have been adopted in maternal vaccine safety research., Methods: A comprehensive search of published literature was undertaken to identify maternal vaccine research studies. PubMed, EMBASE, Web of Science, and Cochrane were searched using a combination of MeSH terms and keyword searches to identify observational or interventional studies that examined vaccine safety in pregnant women with a comparator group. A two-reviewer screening process was undertaken, and a narrative synthesis of the results presented., Results: 14,737 titles were identified from database searches, 435 titles were selected as potentially relevant, 256 were excluded, the remaining 116 papers were included. Influenza vaccine was the most studied (25.0%), followed by TDaP (20.7%) and SARS-CoV-2 (12.9%).Ninety-one studies (78.4%) were conducted in high-income settings. Forty-eight (41.4%) utilised electronic health-records. The majority focused on reporting adverse events of special interest (AESI) in pregnancy (65.0%) alone or in addition to reactogenicity (27.6%). The most frequently reported AESI were preterm birth, small for gestational age and hypertensive disorders. Fewer than 10 studies reported use of GAIA definitions. Gestational age assessment was poorly described; of 39 studies reporting stillbirths 30.8% provided no description of the gestational age threshold., Conclusions: Low-income settings remain under-represented in comparative maternal vaccine safety research. There has been poor uptake of GAIA case definitions. A lack of harmonisation and standardisation persists limiting comparability of the generated safety data., Competing Interests: Financial support for this work was provided by the European and Developing Countries Clinical Trials Partnership. Clare Cutland and Flor Muñoz were involved in leading the GAIA definition development. Hannah Davies is involved in the GAIA definition revision process., (© 2024 The Authors.)

In 2014, the Global Alignment on Immunization safety Assessment in pregnancy consortium (GAIA) was formed, with the goal of developing a harmonized, globally-concerted approach to actively monitor the safety of vaccines in pregnancy. A total of 26 standardized definitions for the classification of adverse events have been developed. The aim of this review was to identify and describe studies undertaken to assess the performance of these definitions. A literature search was undertaken to identify published studies assessing the performance of the definitions, and reference lists were snowballed. Data were abstracted by two investigators and a narrative review of the results is presented. Four studies that have evaluated 13 GAIA case definitions (50%) were identified. Five case definitions have been assessed in high-income settings only. Recommendations have been made by the investigators to improve the performance of the definitions. These include ensuring consistency across definitions, removal of the potential for ambiguity or variations in interpretation and ensuring that higher-level criteria are acceptable at lower levels of confidence. Future research should prioritize the key case definitions that have not been assessed in low- and middle-income settings, as well as the 13 that have not undergone any validation., (© 2023 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Despite the success of COVID-19 vaccines, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern have emerged that can cause breakthrough infections. Although protection against severe disease has been largely preserved, the immunological mediators of protection in humans remain undefined. We performed a substudy on the ChAdOx1 nCoV-19 (AZD1222) vaccinees enrolled in a South African clinical trial. At peak immunogenicity, before infection, no differences were observed in immunoglobulin (Ig)G1-binding antibody titers; however, the vaccine induced different Fc-receptor-binding antibodies across groups. Vaccinees who resisted COVID-19 exclusively mounted FcγR3B-binding antibodies. In contrast, enhanced IgA and IgG3, linked to enriched FcγR2B binding, was observed in individuals who experienced breakthrough. Antibodies unable to bind to FcγR3B led to immune complex clearance and resulted in inflammatory cascades. Differential antibody binding to FcγR3B was linked to Fc-glycosylation differences in SARS-CoV-2-specific antibodies. These data potentially point to specific FcγR3B-mediated antibody functional profiles as critical markers of immunity against COVID-19., (© 2023. The Author(s).)

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., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Shabir Madhi reports financial support was provided by GlaxoSmithKline. Shabir Madhi reports financial support was provided by AstraZeneca. Shabir Madhi reports financial support was provided by BMGF. Shabir Madhi reports financial support was provided by South African Medical Research Council. Shabir Madhi reports financial support was provided by Pfizer. Shabir Madhi reports financial support was provided by Minervax. Shabir Madhi reports financial support was provided by Novavax. Shabir Madhi reports financial support was provided by Providence. Shabir Madhi reports financial support was provided by Greenstone. Shabir Madhi reports financial support was provided by ImmunityBio. Clare L. Cutland reports financial support was provided by BMGF. Clare L. Cutland reports financial support was provided by Pfizer. Clare L. Cutland reports financial support was provided by Biovac. Lee Fairlie reports financial support was provided by South African Medical Research Council. Lee Fairlie reports financial support was provided by Bill and Melinda Gates Foundation. Mookho Malahleha reports financial support was provided by Synergy Biomed Research Institute. Andrew J. Pollard reports financial support was provided by University of Oxford. Andrew J. Pollard reports financial support was provided by Shionogi. Andrew J. Pollard reports financial support was provided by AstraZeneca. Andrew J. Pollard reports financial support was provided by National Institute for Health and Care Research. Qasim Ebrahim Bhorat reports financial support was provided by Wits Health Consortium. Qasim Ebrahim Bhorat reports financial support was provided by Regeneron Pharmaceuticals. Qasim Ebrahim Bhorat reports financial support was provided by GlaxoSmithKline. Qasim Ebrahim Bhorat reports financial support was provided by Avillion. Qasim Ebrahim Bhorat reports financial support was provided by Sanofi. Qasim Ebrahim Bhorat reports financial support was provided by NovoNordisk. Qasim Ebrahim Bhorat reports financial support was provided by Bill & Melinda Gates Foundation. Qasim Ebrahim Bhorat reports financial support was provided by South African Medical Research Council. Qasim Ebrahim Bhorat reports financial support was provided by Novavax. Qasim Ebrahim Bhorat reports financial support was provided by AstraZeneca. Qasim Ebrahim Bhorat reports financial support was provided by Clover BioPharmaceticals. Tonya L. Villafana reports financial support was provided by AstraZeneca. Clare L. Cutland reports a relationship with BMGF that includes: employment and funding grants. Mookho Malahleha reports a relationship with RTI that includes: consulting or advisory. Andrew J. Pollard reports a relationship with UK Joint Committee on Vaccines and Immunization that includes: board membership. Andrew J. Pollard reports a relationship with World Health Organisation SAGE that includes: board membership. Sarah Gilbert reports a relationship with Vaccitech that includes: equity or stocks. Teresa Lambe reports a relationship with Vaccitech that includes: consulting or advisory. Mookho Malahleha reports a relationship with Synergy Biomed Research Institute that includes: board membership, employment, and equity or stocks. Sarah Gilbert has patent issued to Vaccitech. Teresa Lambe has patent issued to Vaccitech., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Pneumococcal conjugate vaccine (PCV) immunisation has reduced vaccine-serotype colonisation and invasive pneumococcal disease in South Africa, providing the opportunity to consider transitioning from a two-dose (2 + 1) to one-dose (1 + 1) primary series and a booster dose., Methods: In this single-centre, open-label, randomised trial done in South Africa, infants aged 35-49 days without HIV infection, without childhood immunisations except for BCG and polio, and with gestation age at delivery of at least 37 weeks of age, a birthweight of at least 2500 g, and weight of at least 3500 g at the time of enrolment were randomly assigned (1:1:1:1:1:1), through block randomisation (block size of 30), to receive a single priming dose of ten-valent PCV (PCV10) or 13-valent PCV (PCV13) at either 6 weeks (6-week 1 + 1 group) or 14 weeks (14-week 1 + 1 group), compared with two priming doses at 6 weeks and 14 weeks (2 + 1 group), followed by a booster dose at 9 months of age in all groups. The primary objective of the trial has been published previously. We report the secondary objective of the effect of alternative doses of PCV10 and PCV13 on serotype-specific Streptococcus pneumoniae colonisation at 9 months, 15 months, and 18 months of age and a further exploratory analysis in which we assessed non-inferiority of serotype-specific serum IgG geometric mean concentrations 1 month after the booster (10 months of age) and the percentage of participants with serotype-specific IgG titre above the putative thresholds associated with a risk reduction of serotype-specific colonisation between the 1 + 1 and 2 + 1 groups for both vaccines. Non-inferiority was established if the lower limit of the 95% CI for the difference between the proportion of participants (1 + 1 group vs 2 + 1 group) above the putative thresholds was greater than or equal to -10%. All analyses were done in the modified intention-to-treat population, which included all participants who received PCV10 or PCV13 according to assigned randomisation group and for whom laboratory results were available. The trial is registered with ClinicalTrials.gov, NCT02943902., Findings: 1564 nasopharyngeal swabs were available for molecular serotyping from 600 infants who were enrolled (100 were randomly assigned to each of the six study groups) between Jan 9 and Sept 20, 2017. There was no significant difference in the prevalence of overall or non-vaccine serotype colonisation between all PCV13 or PCV10 groups. PCV13 serotype colonisation was lower at 15 months of age in the 14-week 1 + 1 group than in the 2 + 1 group (seven [8%] of 85 vs 17 [20%] of 87; odds ratio 0·61 [95% CI 0·38-0·97], p=0·037), but no difference was seen at 9 months (nine [11%] of 86 vs ten [11%] of 89; 0·92 [0·60-1·55], p=0·87) or 18 months (nine [11%] of 85 vs 11 [14%] of 87; 0·78 [0·45-1·22], p=0·61). Compared with the PCV13 2 + 1 group, both PCV13 1 + 1 groups did not meet the non-inferiority criteria for serotype-specific anti-capsular antibody concentrations above the putative thresholds purportedly associated with risk reduction for colonisation; however, the PCV10 14-week 1 + 1 group was non-inferior to the PCV10 2 + 1 group., Interpretation: The serotype-specific colonisation data reported in this study together with the primary immunogenicity endpoints of the control trial support transitioning to a reduced 1 + 1 schedule in South Africa. Ongoing monitoring of colonisation should, however, be undertaken immediately before and after transitioning to a PCV 1 + 1 schedule to serve as an early indicator of whether PCV 1 + 1 could lead to an increase in vaccine-serotype disease., Funding: The Bill & Melinda Gates Foundation., Competing Interests: Declaration of interests GlaxoSmithKline (GSK) awarded grant funding to Wits VIDA for research related to PCVs. Furthermore, GSK and Pfizer have funded Wits VIDA to undertake non-pneumococcal research. However, neither Pfizer nor GSK contributed to the funding of this study. JRD has received grants from the Poliomyelitis Research Foundation, consultation fees from the international AIDS Vaccine Initiative, and payment from Sanofi-Aventis South Africa and Sci Mentum for work not related to this manuscript. CPO has received grants from Pfizer and the Bill & Melinda Gates Foundation, payment from Sanofi-Aventis South Africa, and support from the Gates Foundation to attend a meeting unrelated to this work. SAM has received grants from Pfizer, Minervax, GSK, the Gates Foundation, and the South African Medical Research Council, and he has received honoraria and support to attend a meeting from GSK and MSD unrelated to this work. CLC has received grants from Sanofi and Duetsche Gesellschaft fur Internationale Zusammenarbeit. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: Declaration of interests Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19 (AZD1222). SCG is cofounder of Vaccitech, a collaborator in the early development of this vaccine candidate, and is named as an inventor on a patent covering use of ChAdOx1-vectored vaccines (PCT–GB2012–000467) and a patent application covering this SARS-CoV-2 vaccine (GB2003670.3). TL is named as an inventor on a patent application covering ChAdOx1 nCoV-19 and was a consultant to Vaccitech. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Immunogenicity and safety up to 5 years after administration of 1 or 2 doses of quadrivalent meningococcal serogroup A, C, W, and Y tetanus toxoid conjugate vaccine (MenACWY-TT) given alone or with 13-valent pneumococcal conjugate vaccine (PCV13) in children was investigated., Methods: This phase 3 study randomized healthy 12-24-month-olds to MenACWY-TT at Month 0 (ACWY1d), MenACWY-TT at Months 0 and 2 (ACWY2d), MenACWY-TT and PCV13 at Month 0 (Co-Ad), or PCV13 at Month 0 and MenACWY-TT at Month 2 (PCV13/ACWY). Immune responses 1, 3, and 5 years after primary vaccination were evaluated with serum bactericidal activity using rabbit complement (rSBA) titers ≥ 1:8 and geometric mean titers (GMTs). Evaluation of serious adverse events up to 5 years after primary vaccination are reported., Results: Of the 802 children randomized in the study, 619 completed the study through Year 5. Immune responses after vaccination declined over time but were higher 5 years after vaccination compared with levels before vaccination. At Year 5, the percentages of children with rSBA titers ≥ 1:8 across all serogroups were 20.5 %-58.6 %, 28.4 %-65.8 %, 23.9 %-52.8 %, and 19.4 %-55.8 % in the ACWY1d, ACWY2d, Co-Ad, and PCV13/ACWY groups, respectively. Comparable antibody persistence at Year 5 was observed for participants receiving 1 or 2 doses of MenACWY-TT, although GMTs were elevated in those who received 2 versus 1 dose. The percentage of children with protective antibody titers at Year 5 was similar in participants who received PCV13 and MenACWY-TT compared with that observed for participants who only received 1 or 2 MenACWY-TT doses. No new safety concerns were identified during the study period., Conclusion: Antibody responses persisted in the majority of children up to 5 years after primary vaccination with MenACWY-TT administered in a 1- or 2-dose regimen with or without PCV13, with no new safety concerns identified., Clinicaltrials: gov Identifier NCT01939158; EudraCT number 2013-001083-28., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Respiratory syncytial virus is the second most common cause of infant mortality and a major cause of morbidity and mortality in older adults (aged >60 years). Efforts to develop a respiratory syncytial virus vaccine or immunoprophylaxis remain highly active. 33 respiratory syncytial virus prevention candidates are in clinical development using six different approaches: recombinant vector, subunit, particle-based, live attenuated, chimeric, and nucleic acid vaccines; and monoclonal antibodies. Nine candidates are in phase 3 clinical trials. Understanding the epitopes targeted by highly neutralising antibodies has resulted in a shift from empirical to rational and structure-based vaccine and monoclonal antibody design. An extended half-life monoclonal antibody for all infants is likely to be within 1 year of regulatory approval (from August, 2022) for high-income countries. Live-attenuated vaccines are in development for older infants (aged >6 months). Subunit vaccines are in late-stage trials for pregnant women to protect infants, whereas vector, subunit, and nucleic acid approaches are being developed for older adults. Urgent next steps include ensuring access and affordability of a respiratory syncytial virus vaccine globally. This review gives an overview of respiratory syncytial virus vaccines and monoclonal antibodies in clinical development highlighting different target populations, antigens, and trial results., Competing Interests: Declaration of interests UMCU received minor funding from The Bill & Melinda Gates Medical Research Institute. DMW has received consulting fees from Pfizer, Merck, Affinivax, and Matrivax, unrelated to this manuscript; and is a principal investigator with grant support from Pfizer and Merck to Yale University, unrelated to this manuscript. NIM has regular interaction with pharameutical and other industrial partners: UMC Utrecht has received fees for invited lectures by Abbvie, Merck, and Sanofi. LB has regular interaction with pharmaceutical and other industrial partners. BSG is an inventor of patents for RSV vaccines using the stabilised prefusion F protein. AM has received research grants from National Institutes of Health, Janssen, and Merck institution; fees for participation in advisory boards from Janssen, Sanofi-Pasteur, and Merck; and fees for educational lectures from Sanofi-Pasteur and AstraZeneca. TJR was financially supported by the Intramural Program of the National Institute of Allergy & Infectious Diseases, National Institute of Health. BSG was financially supported by the Intramural Program of the National Institute of Allergy & Infectious Diseases, National Institute of Health. UJB was financially supported by the Intramural Program of the National Institute of Allergy & Infectious Diseases, National Institute of Health. UMCU has received major funding (>€100 000 per industrial partner) for investigator-initiated studies from AbbVie, MedImmune, Janssen, Pfizer, the Bill & Melinda Gates Foundation, and MeMed Diagnostics. UMCU has received major cash or in-kind funding as part of the public private partnership IMI-funded RESCEU project from GSK, Novavax, Janssen, AstraZeneca, Pfizer, and Sanofi. UMCU has received major funding by Julius Clinical for participating in the INFORM study sponsored by MedImmune. UMCU has received minor funding for participation in trials by Regeneron and Janssen from 2015-17 (total annual estimate less than €20 000). UMCU received minor funding for consultation and invited lectures by AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, Novavax, Pfizer, and Janssen (total annual estimate less than €20 000). Dr. Bont is the founding chairman of the ReSViNET Foundation., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Influenza vaccination during pregnancy reduces influenza-associated illness in the women and their infants, but effectiveness estimates against influenza-associated hospitalization are limited and lacking from settings with high human immunodeficiency virus (HIV) infection prevalence. We assessed the effect of maternal vaccination in HIV-uninfected women and women with HIV in preventing influenza-associated hospitalizations in infants and the women., Methods: During 2015-2018, influenza vaccination campaigns targeting pregnant women were augmented at selected antenatal clinics; these were coupled with prospective hospital-based surveillance for acute respiratory or febrile illness in infants aged <6 months and cardiorespiratory illness among pregnant or postpartum women. Vaccine effectiveness (VE) was assessed using a test-negative case-control study., Results: Overall, 71 influenza-positive and 371 influenza-negative infants were included in the analysis; mothers of 26.8% of influenza-positive infants were vaccinated during pregnancy compared with 35.6% of influenza-negative infants, corresponding to an adjusted VE (aVE) of 29.0% (95% confidence interval [CI], -33.6% to 62.3%). When limited to vaccine-matched strains, aVE was 65.2% (95% CI, 11.7%-86.3%). For maternal hospitalizations, 56 influenza-positive and 345 influenza-negative women were included in the analysis, with 28.6% of influenza-positive women being vaccinated compared with 38.3% of influenza-negatives, for an aVE of 46.9% (95% CI, -2.8% to 72.5%). Analysis restricted to HIV-uninfected women resulted in 82.8% (95% CI, 40.7%-95.0%) aVE. No significant aVE (-32.5% [95% CI, -208.7% to 43.1%]) was detected among women with HIV., Conclusions: Influenza vaccination during pregnancy prevented influenza-associated hospitalizations among young infants when infected with vaccine strains and among HIV-uninfected women., Competing Interests: Potential conflicts of interest. M. C. N. reports grants to institution from BMGF, the European and Developing Countries Clinical Trials Partnership (EDCTP), Pfizer, AstraZeneca, and Sanofi, and personal honoraria received from Pfizer and Sanofi, unrelated to the manuscript. S. A. M. reports grants to institution from BMGF, the South African Medical Research Council, Novavax, Pfizer, Gritstone (PATH), Providence, Johnson & Johnson, AstraZeneca, EDCTP, GSK, and Minervax, and personal honoraria received from BMGF unrelated to the manuscript. C. C. reports grants to institution from Sanofi, Advanced Vaccine Initiative, and the CDC, and payment of travel costs from Parexel. H. J. Z. reports grants to institution from BMGF, the South African Medical Research Council, Novavax, Pfizer, AstraZeneca, MSD, and EDCTP. All other authors report no potential conflicts., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Within 2 years after the start of the coronavirus disease 2019 (COVID-19) pandemic, novel severe acute respiratory syndrome coronavirus 2 vaccines were developed, rigorously evaluated in large phase 3 trials, and administered to more than 5 billion individuals globally. However, adverse events of special interest (AESIs) have been described post-implementation, including myocarditis after receipt of messenger RNA (mRNA) vaccines and thrombosis with thrombocytopenia syndrome after receipt of adenoviral vector vaccines. AESIs are rare (<1 to 10/100 000 vaccinees) and less frequent than COVID-19 complications, though they have associated morbidity and mortality. The diversity of COVID-19 vaccine platforms (eg, mRNA, viral vector, protein) and rates of AESIs both between and within platforms (eg, higher rate of myocarditis after mRNA-1273 vs BNT162b2 vaccines) present an important opportunity to advance vaccine safety science. The International Network of Special Immunization Services has been formed with experts in vaccine safety, systems biology, and other relevant disciplines to study cases of AESIs and matched controls to uncover the pathogenesis of rare AESIs and inform vaccine development., Competing Interests: Potential conflicts of interest. K. A. T. reports funding from the Canadian Institutes of Health Research and Public Health Agency of Canada for safety evaluation of coronavirus disease 2019 (COVID-19) vaccines and grants from GlaxoSmithKline outside the submitted work. O. L. is a named inventor on patents relating to adjuvants and human in vitro systems that predict vaccine safety assessments and reports grants for the Precision Vaccines Program from the Boston Children’s Hospital Department of Pediatrics and the Chief Scientific Office and consulting fees from Moody’s analytics. C. B. C. reports grants and contracts from the NIH and CDC for vaccine clinical trials including NIH Vaccine and Treatment Evaluation Unit (including the Moderna COVE study, Janssen ENSEMBLE study, Moderna KidCOVE study) and CDC Clinical Immunization Safety Assessment Network; grants from Merck; royalties for contributions to the UpToDate program; multiple small honoraria for lectures on COVID-19 vaccines and other vaccines; consultation fees from Altimmune (COVID-19 vaccine development), Janssen (respiratory syncytial virus vaccine development), Astellas (clinical trial data and safety monitoring board), Horizon Pharma (consultation related to care of children with chronic granulomatous disease), and Vir (influenza monoclonal antibody development); payment for expert testimony from multiple legal firms for general medical malpractice; US patent 10,981,979 B2; and serving as the president of the Pediatric Infectious Diseases Society. K. G. reports grants from the Task Force for Global Health and the CDC via the Global Vaccine Data Network for sentinel surveillance and personal fees from the CDC via the Global Vaccine Data Network for vaccine safety training materials. C. L. C. reports a grant from GAVI, the Vaccine Alliance, for vaccine safety surveillance and serving as a member of the Brighton Collaboration Scientific committee and the Institutional Biosafety committee. G. A. P. reports funding from ICW Ventures and the NIH (AI 48793, AI 33144, and AI 132348); consulting fees from Contec, Inc, 3D Communications, AstraZeneca UK Ltd, Bank of America Corporation, Eli Lily and Company, Emergent BioSolutions, Exelixis Inc, ExpertConnect, Genevant Sciences, Inc, GlaxoSmithKline, Janssen Global Services, LLC, Janssen Research & Development, LLC, Medicago USA, Medscape, LLC, Merck, Regeneron Pharmaceuticals Inc, Sanofi Pasteur SA, Syneos Health, and Vyriad; and participation on a data safety monitoring or advisory board for 3D Communications, AstraZeneca UK Ltd, Bavarian Nordic A/S, Dynavax Technologies, Genentech, Inc, GlaxoSmithKline, Janssen Global Services, LLC, and Janssen Pharmaceuticals, Inc. N. C. reports a Medical Research Future Fund grant and serving on a government advisory committee for the Australian Technical Advisory Group on Immunisation-ATAGI. B. C. reports a CDC grant and serving as a board member for the Rare Disease Foundation. R. T. C. reports grants from the Coalition for Epidemic Preparedness and Innovation and the CDC; travel support from Elsevier; honoraria payments from the Brighton Collaboration; serving as the scientific director at the Brighton Collaboration; and serving as a co-lead on the COVAX Vaccine Safety Working Group. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

The WHO Global Vaccine Safety Multi-Country Collaboration study on safety in pregnancy aims to estimate the minimum detectable risk for selected perinatal and neonatal outcomes and assess the applicability of standardized case definitions for study outcomes and maternal immunization in low- and middle-income countries (LMICs). This paper documents the operational lessons learned from the study. A prospective observational study was conducted across 21 hospitals in seven countries. All births occurring at sites were screened to identify select perinatal and neonatal outcomes from May 2019 to August 2020. Up to 100 cases per outcome were recruited to assess the applicability of standardized case definitions. A multi-pronged study quality assurance plan was implemented. The impact of the COVID-19 pandemic on site functioning and project implementation was also assessed. Multi-layered ethics and administrative approvals, limited clinical documentation, difficulty in identifying outcomes requiring in-hospital follow-up, and poor quality internet connectivity emerged as important barriers to study implementation. Use of electronic platforms, application of a rigorous quality assurance plan with frequent interaction between the central and site teams helped improve data quality. The COVID-19 pandemic disrupted data collection for up to 6 weeks in some sites. Our study succeeded in establishing an international hospital-based surveillance network for evaluating perinatal and neonatal outcomes using common study protocol and procedures in geographically diverse sites with differing levels of infrastructure, clinical and health-utilization practices. The enhanced surveillance capacity of participating sites shall help support future pharmacovigilance efforts for pregnancy interventions., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Transplacental hMPV-neutralizing antibody transfer was reduced from mothers living with HIV-1. However, a comparison of antibody titers at birth between hMPV hospitalization cases at <6 months and matched controls suggested that reduced maternal antibody might not be the primary cause of the previously reported elevated hMPV risk in HIV-1-exposed infants., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Disease X represents a yet unknown human pathogen which has potential to cause a serious international epidemic or pandemic. The COVID-19 pandemic has illustrated that despite being at increased risk of severe disease compared with the general population, pregnant women were left behind in the development and implementation of vaccination, resulting in conflicting communications and changing guidance about vaccine receipt in pregnancy. Based on the COVID-19 experience, the COVAX Maternal Immunization Working Group have identified three key factors and five broad focus topics for consideration when proactively planning for a disease X pandemic, including 10 criteria for evaluating pandemic vaccines for potential use in pregnant women. Prior to any disease X pandemic, collaboration and coordination are needed to close the pregnancy data gap which is currently a barrier to gender equity in health innovation, which will aid in allowing timely access to life-saving interventions including vaccines for pregnant women and their infants., Competing Interests: FM—member DSMB Pfizer, Moderna, Meissa Vaccines, Virometix, US National Institutes of Health (NIH); Research support Pfizer, Gilead, US Centers for Disease Control and Prevention (CDC), US National Institutes of Health (NIH) and Infectious Diseases Clinical Research Center (IDCRC); Member Immunization Expert Group at the American College of Obstetrics and Gynecology (ACOG), Member Committee of Infectious Diseases (COID) of the American Academy of Pediatrics (AAP), Member Executive Committee of the Society of Infectious Diseases (SOID) of the AAP. CC—scientific advisor for Pfizer's maternal immunization work. Research and training support from BMGF, Sanofi. CJ—investigator for clinical trials sponsored by Pfizer and Medicago; participation of data safety monitoring board or advisory board for MSD, Pfizer, and Sanofi. BK—investigator for clinical trials sponsored by Pfizer; member of ad hoc Scientific Advisory Committees for GSK, Pfizer, Johnson & Johnson and member of Independent Data Monitoring Committee J&J; Director of IMPRINT https://www.imprint-network.co.uk. AS—research support from the Bill & Melinda Gates Foundation. GS—chair of Independent Data Monitoring Committees for GlaxoSmithKline (RSV vaccine) and Pfizer (Group B Strep vaccine), Member DSMB National Cancer Institute (HPV vaccine), Member Immunization Expert Group at the American College of Obstetrics and Gynecology. Investigator for clinical trials sponsored by Novavax, GlaxoSmithKline, Regeneron, Pfizer, NIH, and US Centers for Disease Control & Prevention. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Munoz, Cutland, Jones, Kampmann, Khalil, Sevene, Stergachis, Swamy, Voss and Sobanjo-ter Meulen.)

Vitamin D regulates the master iron hormone hepcidin, and iron in turn alters vitamin D metabolism. Although vitamin D and iron deficiency are highly prevalent globally, little is known about their interactions in Africa. To evaluate associations between vitamin D and iron status we measured markers of iron status, inflammation, malaria parasitemia, and 25-hydroxyvitamin D (25(OH)D) concentrations in 4509 children aged 0.3 months to 8 years living in Kenya, Uganda, Burkina Faso, The Gambia, and South Africa. Prevalence of iron deficiency was 35.1%, and prevalence of vitamin D deficiency was 0.6% and 7.8% as defined by 25(OH)D concentrations of <30 nmol/L and <50 nmol/L, respectively. Children with 25(OH)D concentrations of <50 nmol/L had a 98% increased risk of iron deficiency (OR 1.98 [95% CI 1.52, 2.58]) compared to those with 25(OH)D concentrations >75 nmol/L. 25(OH)D concentrations variably influenced individual markers of iron status. Inflammation interacted with 25(OH)D concentrations to predict ferritin levels. The link between vitamin D and iron status should be considered in strategies to manage these nutrient deficiencies in African children.

From April to September 2020, we investigated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in a cohort of 396 healthcare workers (HCWs) from 5 departments at Chris Hani Baragwanath Hospital, South Africa. Overall, 34.6% of HCWs had polymerase chain reaction-confirmed SARS-CoV-2 infection (132.1 [95% confidence interval, 111.8-156.2] infections per 1000 person-months); an additional 27 infections were identified by serology. HCWs in the internal medicine department had the highest rate of infection (61.7%). Among polymerase chain reaction-confirmed cases, 10.4% remained asymptomatic, 30.4% were presymptomatic, and 59.3% were symptomatic., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Licensure of a group B Streptococcus (GBS) polysaccharide-protein conjugate vaccine for protecting infants against invasive GBS disease (IGbsD) will likely need to be based on demonstrating vaccine safety in pregnant women, and benchmarking immunogenicity against a serological threshold associated with risk reduction of IGbsD. We investigated the association between naturally derived GBS serotype Ia and III IgG and risk reduction of IGbsD in infants ≤90 days of age., Methods: In a matched case-control study, IGbsD cases were identified from a cohort of 38 233 mother-newborn dyads. Mothers colonized vaginally with serotype Ia or III at birth and their healthy infants were eligible as matched controls. GBS serotype-specific anticapsular immunoglobulin G (IgG) was measured on maternal and cord blood/infant sera by multiplex Luminex assay, and the IgG threshold associated with 90% risk reduction of IGbsD was derived by estimating absolute disease risk., Results: In infants born at ≥34 weeks' gestational age, cord-blood IgG geometric mean concentrations (GMCs) were lower in cases than controls for serotypes Ia (0.05 vs 0.50 µg/mL; P = .004) and III (0.20 vs 0.38 µg/mL; P = .078). Cord-blood IgG concentrations ≥1.04 and ≥1.53 µg/mL were associated with 90% risk reduction of serotype Ia and III IGbsD, respectively. The maternal sera IgG threshold associated with 90% risk reduction was ≥2.31 µg/mL and ≥3.41 µg/mL for serotypes Ia and III, respectively., Conclusions: The threshold associated with a reduced risk for serotype Ia and III IGbsD identified on infant sera supports the case for licensure of a GBS polysaccharide-protein conjugate vaccine based on an immunogenicity evaluation benchmarked against the defined thresholds., Clinical Trials Registration: NCT02215226., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

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., Competing Interests: Declaration of interests Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19 (AZD1222). AstraZeneca reviewed the data from the trial and the final manuscript before submission, but the authors retained editorial control. SCG is cofounder of Vaccitech, a collaborator in the early development of this vaccine candidate, and is named as an inventor on a patent covering use of ChAdOx1-vectored vaccines (PCT/GB2012/000467) and a patent application covering this SARS-CoV-2 vaccine (GB2003670.3). TL is named as an inventor on a patent application covering ChAdOx1 nCoV-19 and was a consultant to Vaccitech. TLV and JV are employees of AstraZeneca. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Children living in sub-Saharan Africa have a high burden of rickets and infectious diseases, conditions that are linked to vitamin D deficiency. However, data on the vitamin D status of young African children and its environmental and genetic predictors are limited. We aimed to examine the prevalence and predictors of vitamin D deficiency in young African children., Methods: We measured 25-hydroxyvitamin D (25(OH)D) and typed the single nucleotide polymorphisms, rs4588 and rs7041, in the GC gene encoding the vitamin D binding protein (DBP) in 4509 children aged 0-8 years living in Kenya, Uganda, Burkina Faso, The Gambia and South Africa. We evaluated associations between vitamin D status and country, age, sex, season, anthropometric indices, inflammation, malaria and DBP haplotypes in regression analyses., Results: Median age was 23.9 months (interquartile range [IQR] 12.3, 35.9). Prevalence of vitamin D deficiency using 25(OH)D cut-offs of < 30 nmol/L and < 50 nmol/L was 0.6% (95% CI 0.4, 0.9) and 7.8% (95% CI 7.0, 8.5), respectively. Overall median 25(OH)D level was 77.6 nmol/L (IQR 63.6, 94.2). 25(OH)D levels were lower in South Africa, in older children, during winter or the long rains, and in those with afebrile malaria, and higher in children with inflammation. 25(OH)D levels did not vary by stunting, wasting or underweight in adjusted regression models. The distribution of Gc variants was Gc1f 83.3%, Gc1s 8.5% and Gc2 8.2% overall and varied by country. Individuals carrying the Gc2 variant had lower median 25(OH)D levels (72.4 nmol/L (IQR 59.4, 86.5) than those carrying the Gc1f (77.3 nmol/L (IQR 63.5, 92.8)) or Gc1s (78.9 nmol/L (IQR 63.8, 95.5)) variants., Conclusions: Approximately 0.6% and 7.8% of young African children were vitamin D deficient as defined by 25(OH)D levels < 30 nmol/L and < 50 nmol/L, respectively. Latitude, age, season, and prevalence of inflammation and malaria should be considered in strategies to assess and manage vitamin D deficiency in young children living in Africa.

Background: Assessment of the safety and efficacy of vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in different populations is essential, as is investigation of the efficacy of the vaccines against emerging SARS-CoV-2 variants of concern, including the B.1.351 (501Y.V2) variant first identified in South Africa., Methods: We conducted a multicenter, double-blind, randomized, controlled trial to assess the safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) in people not infected with the human immunodeficiency virus (HIV) in South Africa. Participants 18 to less than 65 years of age were assigned in a 1:1 ratio to receive two doses of vaccine containing 5×10 10 viral particles or placebo (0.9% sodium chloride solution) 21 to 35 days apart. Serum samples obtained from 25 participants after the second dose were tested by pseudovirus and live-virus neutralization assays against the original D614G virus and the B.1.351 variant. The primary end points were safety and efficacy of the vaccine against laboratory-confirmed symptomatic coronavirus 2019 illness (Covid-19) more than 14 days after the second dose., Results: Between June 24 and November 9, 2020, we enrolled 2026 HIV-negative adults (median age, 30 years); 1010 and 1011 participants received at least one dose of placebo or vaccine, respectively. Both the pseudovirus and the live-virus neutralization assays showed greater resistance to the B.1.351 variant in serum samples obtained from vaccine recipients than in samples from placebo recipients. In the primary end-point analysis, mild-to-moderate Covid-19 developed in 23 of 717 placebo recipients (3.2%) and in 19 of 750 vaccine recipients (2.5%), for an efficacy of 21.9% (95% confidence interval [CI], -49.9 to 59.8). Among the 42 participants with Covid-19, 39 cases (95.1% of 41 with sequencing data) were caused by the B.1.351 variant; vaccine efficacy against this variant, analyzed as a secondary end point, was 10.4% (95% CI, -76.8 to 54.8). The incidence of serious adverse events was balanced between the vaccine and placebo groups., Conclusions: A two-dose regimen of the ChAdOx1 nCoV-19 vaccine did not show protection against mild-to-moderate Covid-19 due to the B.1.351 variant. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT04444674; Pan African Clinical Trials Registry number, PACTR202006922165132)., (Copyright © 2021 Massachusetts Medical Society.)

Malaria and iron deficiency (ID) are common and interrelated public health problems in African children. Observational data suggest that interrupting malaria transmission reduces the prevalence of ID 1 . To test the hypothesis that malaria might cause ID, we used sickle cell trait (HbAS, rs334 ), a genetic variant that confers specific protection against malaria 2 , as an instrumental variable in Mendelian randomization analyses. HbAS was associated with a 30% reduction in ID among children living in malaria-endemic countries in Africa (n = 7,453), but not among individuals living in malaria-free areas (n = 3,818). Genetically predicted malaria risk was associated with an odds ratio of 2.65 for ID per unit increase in the log incidence rate of malaria. This suggests that an intervention that halves the risk of malaria episodes would reduce the prevalence of ID in African children by 49%.

Background: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4-12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered., Methods: We present data from three single-blind randomised controlled trials-one phase 1/2 study in the UK (COV001), one phase 2/3 study in the UK (COV002), and a phase 3 study in Brazil (COV003)-and one double-blind phase 1/2 study in South Africa (COV005). As previously described, individuals 18 years and older were randomly assigned 1:1 to receive two standard doses of ChAdOx1 nCoV-19 (5 × 10 10 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 10 10 viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005)., Findings: Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4-74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3-85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59-0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3-91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0-69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18-55 years (GMR 2·32 [2·01-2·68])., Interpretation: The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose., Funding: UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Despite significant progress in reaching some milestones of the United Nations Sustainable Development Goals, neonatal and early infant morbidity and mortality remain high, and maternal health remains suboptimal in many countries. Novel and improved preventative strategies with the potential to benefit pregnant women and their infants are needed, with maternal and neonatal immunization representing effective approaches. Experts from immunology, vaccinology, infectious diseases, clinicians, industry, public health, and vaccine-related social sciences convened at the 5th International Neonatal and Maternal Immunization Symposium (INMIS) in Vancouver, Canada, from 15 to 17 September 2019. We critically evaluated the lessons learned from recent clinical studies, presented cutting-edge scientific progress in maternal and neonatal immunology and vaccine development, and discussed maternal and neonatal immunization in the broader context of infectious disease epidemiology and public health. Focusing on practical aspects of research and implementation, we also discussed the safety, awareness, and perception of maternal immunization as an existing strategy to address the need to improve maternal and neonatal health worldwide. The symposium provided a comprehensive scientific and practical primer as well as an update for all those with an interest in maternal and neonatal infection, immunity, and vaccination. The summary presented here provides an update of the current status of progress in maternal and neonatal immunization., (Copyright © 2021 Sadarangani et al.)

Background: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials., Methods: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 10 10 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674., Findings: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; p interaction =0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation., Interpretation: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials., Funding: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

In December 2019 a new coronavirus (CoV) emerged as a human pathogen, SARS-CoV-2. There are few data on human coronavirus infections among individuals living with HIV. In this study we probed the role of pneumococcal coinfections with seasonal CoVs among children living with and without HIV hospitalized for pneumonia. We also described the prevalence and clinical manifestations of these infections. A total of 39,836 children who participated in a randomized, double-blind, placebo-controlled clinical trial on the efficacy of a 9-valent pneumococcal conjugate vaccine (PCV9) were followed for lower respiratory tract infection hospitalizations until 2 years of age. Nasopharyngeal aspirates were collected at the time of hospitalization and were screened by PCR for four seasonal CoVs. The frequency of CoV-associated pneumonia was higher in children living with HIV (19.9%) than in those without HIV (7.6%, P  < 0.001). Serial CoV infections were detected in children living with HIV. The case fatality risk among children with CoV-associated pneumonia was higher in those living with HIV (30.4%) than without HIV (2.9%, P  = 0.001). C-reactive protein and procalcitonin levels were elevated in 36.8% (≥40 mg/liter) and 64.7% (≥0.5 ng/ml), respectively, of the fatal cases living with HIV. Among children without HIV, there was a 64.0% (95% CI: 22.9% to 83.2%) lower incidence of CoV-associated pneumonia hospitalizations among PCV9 recipients compared to placebo recipients. These data suggest that Streptococcus pneumoniae infections might have a role in the development of pneumonia associated with endemic CoVs, that PCV may prevent pediatric CoV-associated hospitalization, and that children living with HIV with CoV infections develop more severe outcomes. IMPORTANCE SARS-CoV-2 may cause severe hospitalization, but little is known about the role of secondary bacterial infection in these severe cases, beyond the observation of high levels of reported inflammatory markers, associated with bacterial infection, such as procalcitonin. We did a secondary analysis of a double-blind randomized trial of PCV to examine its impact on human CoV infections before the pandemic. We found that both children living with and without HIV randomized to receive PCV had evidence of less hospitalization due to seasonal CoV, suggesting that pneumococcal coinfection may play a role in severe hospitalized CoV infections., (Copyright © 2021 Nunes et al.)

Background: Routine childhood immunisation with pneumococcal conjugate vaccine (PCV) has changed the epidemiology of pneumococcal disease across age groups, providing an opportunity to reconsider PCV dosing schedules. We aimed to evaluate the post-booster dose immunogenicity of ten-valent (PCV10) and 13-valent (PCV13) PCVs between infants randomly assigned to receive a single-dose compared with a two-dose primary series., Methods: We did an open-label, non-inferiority, randomised study in HIV-unexposed infants at a single centre in Soweto, South Africa. Infants were randomly assigned to receive one priming dose of PCV10 or PCV13 at ages 6 weeks (6w + 1 PCV10 and 6w + 1 PCV13 groups) or 14 weeks (14w + 1 PCV10 and 14w + 1 PCV13 groups) or two priming doses of PCV10 or PCV13, one each at ages 6 weeks and 14 weeks (2 + 1 PCV10 and 2 + 1 PCV13 groups); all participants then received a booster dose of PCV10 or PCV13 at 40 weeks of age. The primary endpoint was geometric mean concentrations (GMCs) of serotype-specific IgG 1 month after the booster dose, which was assessed in all participants who received PCV10 or PCV13 as per the assigned randomisation group and for whom laboratory results were available at that timepoint. The 1 + 1 vaccine schedule was considered non-inferior to the 2 + 1 vaccine schedule if the lower bound of the 96% CI for the GMC ratio was greater than 0·5 for at least ten PCV13 serotypes and eight PCV10 serotypes. Safety was a secondary endpoint. This trial is registered with ClinicalTrials.gov (NCT02943902) and is ongoing., Findings: Of 1695 children assessed, 600 were enrolled and randomly assigned to one of the six groups between Jan 9 and Sept 20, 2017; 542 were included in the final analysis of the primary endpoint (86-93 per group). For both PCV13 and PCV10, a 1+1 dosing schedule (either beginning at 6 or 14 weeks) was non-inferior to a 2 + 1 schedule. For PCV13, the lower limit of the 96% CI for the ratio of GMCs between the 1 + 1 and 2 + 1 groups was higher than 0·5 for ten serotypes in the 6w+1 group (excluding 6B, 14, and 23F) and 11 serotypes in the 14w + 1 group (excluding 6B and 23F). For PCV10, the lower limit of the 96% CI for the ratio of GMCs was higher than 0·5 for all ten serotypes in the 6w+1 and 14w + 1 groups. 84 serious adverse events were reported in 72 (12%) of 600 participants. 15 occurred within 28 days of vaccination, but none were considered to be related to PCV injection. There were no cases of culture-confirmed invasive pneumococcal disease., Interpretation: The non-inferiority in post-booster immune responses following a single-dose compared with a two-dose primary series of PCV13 or PCV10 indicates the potential for reducing PCV dosing schedules from a 2 + 1 to 1 + 1 series in low-income and middle-income settings with well established PCV immunisation programmes., Funding: The Bill & Melinda Gates Foundation (OPP1 + 152352)., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background : We evaluated bacterial nasopharyngeal carriage (NPC) prevalence and cumulative acquisition following 7-valent pneumococcal conjugate vaccine (PCV7) or pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) administration. Methods : Participants were children from two clinical trials in a South African center who received PCV7 (n = 250) or PHiD-CV (n = 100) at ~6 weeks, ~14 weeks, and ~9-10 months of age, and were enrolled between Dec2009-Apr2010 and Mar2009-May2010 in the PCV7 and PHiD-CV studies, respectively. Sample collection, most microbiological assessments, and data re-analysis methods were identical. Results : NPC prevalence of any pneumococcal serotype was 18.5% and 17.0% at pre-vaccination, and 63.1% and 67.3% in 24-27 month-old children among PCV7 and PHiD-CV recipients, respectively. In 24-27 month-old children, 96.1% and 99.0% of PCV7 and PHiD-CV recipients had acquired ≥1 pneumococcal serotype, 53.7% and 62.9% ≥1 PCV7 serotype, 1.5%, and 3.1% ≥1 of serotypes 1, 5 or 7F, 23.2% and 19.6% serotype 6A, 23.2% and 21.7% serotype 19A, 88.7%, and 91.0% H. influenzae , and 50.3% and 62.9% Staphylococcus aureus , respectively. Conclusions : This analysis of two concurrent clinical trials did not reveal differences in bacterial NPC prevalence or acquisition in PCV7- and PHiD-CV-vaccinated children. Trial registration : South African National Clinical Trial Register (NHREC DOH-27-0511-299); ClinicalTrials.gov (NCT00829010).

Background: A key consideration for expanding recommendations for influenza vaccination is a robust assessment of immunogenicity and efficiency of transplacental antibody transfer after maternal vaccination., Methods: We pooled data from two trials of maternal influenza vaccination to analyze vaccine immunogenicity with more power than either trial had alone. We compared hemagglutination-inhibition (HAI) titers and titer factor change for women and their infants between trial arms using t-tests; maternal and infant putative seroprotective titers (HAI ≥ 1:40) within each trial arm and maternal seroconversion between trial arms using exact tests; and transplacental antibody transfer between trial arms using t-tests. We used marginal linear models and generalized estimating equations to examine the impact of time between maternal vaccination and delivery on transplacental antibody transfer, infant titers, and infant seroprotection., Results: For all vaccine components (A/H1N1, A/H3N2, and Type B), >80% of vaccinated women had seroprotective titers, >60% of them seroconverted, and >50% of their infants were born with seroprotective titers. These immunogenicity outcomes occurred more often in vaccine recipients and their infants than in controls. No difference in efficiency of transplacental antibody transfer was observed between vaccine recipients and controls., Conclusions: Our results provide robust support for further expansion of maternal influenza vaccination recommendations., Clinical Trials Registration: NCT01430689 and NCT01306669., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Respiratory syncytial virus (RSV) is the dominant cause of severe lower respiratory tract infection in infants, with the most severe cases concentrated among younger infants., Methods: Healthy pregnant women, at 28 weeks 0 days through 36 weeks 0 days of gestation, with an expected delivery date near the start of the RSV season, were randomly assigned in an overall ratio of approximately 2:1 to receive a single intramuscular dose of RSV fusion (F) protein nanoparticle vaccine or placebo. Infants were followed for 180 days to assess outcomes related to lower respiratory tract infection and for 364 days to assess safety. The primary end point was RSV-associated, medically significant lower respiratory tract infection up to 90 days of life, and the primary analysis of vaccine efficacy against the primary end point was performed in the per-protocol population of infants (prespecified criterion for success, lower bound of the 97.52% confidence interval [CI] of ≥30%)., Results: A total of 4636 women underwent randomization, and there were 4579 live births. During the first 90 days of life, the percentage of infants with RSV-associated, medically significant lower respiratory tract infection was 1.5% in the vaccine group and 2.4% in the placebo group (vaccine efficacy, 39.4%; 97.52% CI, -1.0 to 63.7; 95% CI, 5.3 to 61.2). The corresponding percentages for RSV-associated lower respiratory tract infection with severe hypoxemia were 0.5% and 1.0% (vaccine efficacy, 48.3%; 95% CI, -8.2 to 75.3), and the percentages for hospitalization for RSV-associated lower respiratory tract infection were 2.1% and 3.7% (vaccine efficacy, 44.4%; 95% CI, 19.6 to 61.5). Local injection-site reactions among the women were more common with vaccine than with placebo (40.7% vs. 9.9%), but the percentages of participants who had other adverse events were similar in the two groups., Conclusions: RSV F protein nanoparticle vaccination in pregnant women did not meet the prespecified success criterion for efficacy against RSV-associated, medically significant lower respiratory tract infection in infants up to 90 days of life. The suggestion of a possible benefit with respect to other end-point events involving RSV-associated respiratory disease in infants warrants further study. (Funded by Novavax and the Bill and Melinda Gates Foundation; ClinicalTrials.gov NCT02624947.)., (Copyright © 2020 Massachusetts Medical Society.)

This analysis includes pooled data from 2 placebo-controlled maternal influenza immunization trials, with a separate analysis on a meningococcal conjugate vaccine-controlled maternal influenza immunization trial. Maternal influenza immunization was not associated with infant or maternal all-cause mortality in placebo-controlled trials. In the meningococcal conjugate vaccine-controlled trial, there were fewer deaths during low or any influenza circulation weeks among infants whose mothers received meningococcal conjugate vaccine. ClinicalTrials.gov identifiers: NCT01430689, NCT01034254 and NCT02465190.

Vaccines designed for use in pregnancy and vaccine trials specifically involving pregnant women are rapidly expanding. One of the key challenges in designing maternal immunization trials is that developing exclusion criteria requires understanding and quantifying the background risk for adverse pregnancy outcomes in the pregnancy being studied, which can occur independent of any intervention and be unrelated to vaccine administration. The Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA) project has developed and published case definitions and guidelines for data collection, analysis, and evaluation of maternal immunization safety in trials involving pregnant women. Complementing this work, we sought to understand how to best assess obstetric risk of adverse outcomes and differentiate it from the assessment of vaccine safety. Quantification of obstetric risk is based on prior and current obstetric, and maternal medical history. We developed a step-wise approach to evaluate and quantify obstetric and maternal risk factors in pregnancy based on review of published literature and guidelines, and critically assessed these factors in the context of designing inclusion and exclusion criteria for maternal vaccine studies. We anticipate this risk assessment evaluation may assist clinical trialists with study design decisions, including selection of exclusion criteria for vaccine trials involving pregnant women, consideration of sub-group classification, such as high or low risk subjects, or schedule considerations, such as preferred trimester of gestation for an intervention during pregnancy. Additionally, this tool may be utilized in data stratification at time of study analyses., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Linda O Eckert: Site investigator: Novavax Trial. Received no personal funding for these activities. Christine E Jones: Investigator for clinical trials done on behalf of her institutions, sponsored by vaccine manufacturers, but receives no personal funding for these activities. Alisa Kachikis: Site investigator: Novavax Trial but receives no personal funding for these activities. Advisory Boards on Maternal Immunization for GSK and Pfizer. Azucena Bardaji: None]., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Maternal influenza immunisation can reduce morbidity and mortality associated with influenza infection in pregnant women and young infants. We aimed to determine the vaccine efficacy of maternal influenza immunisation against maternal and infant PCR-confirmed influenza, duration of protection, and the effect of gestational age at vaccination on vaccine efficacy, birth outcomes, and infant growth up to 6 months of age., Methods: We did a pooled analysis of three randomised controlled trials done in Nepal (2011-2014), Mali (2011-2014), and South Africa (2011-2013). Pregnant women, gestational age 17-34 weeks in Nepal, 28 weeks or more in Mali, and 20-36 weeks in South Africa, were enrolled. Women were randomly assigned 1:1 to a study group, in which they received trivalent inactivated influenza vaccine (IIV) in all three trials, or a control group, in which they received saline placebo in Nepal and South Africa or quadrivalent meningococcal conjugate vaccine in Mali. Enrolment at all sites was complete by April 24, 2013. Infants and women were assessed for respiratory illness, and samples from those that met the case definition were tested for influenza by PCR testing. Growth measurements, including length and weight, were obtained at birth at all sites, at 24 weeks in South Africa, and at 6 months in Nepal and Mali. The three trials are registered with ClinicalTrials.gov, numbers NCT01430689, NCT01034254, and NCT02465190., Findings: 10 002 women and 9800 liveborn infants were included. Pooled efficacy of maternal vaccination to prevent infant PCR-confirmed influenza up to 6 months of age was 35% (95% CI 19 to 47). The pooled estimate was 56% (28 to 73) within the first 2 months of life, 39% (11 to 58) between 2 and 4 months, and 19% (-9 to 40) between 4 and 6 months. In women, from enrolment during pregnancy to the end of follow-up at 6 months postpartum, the vaccine was 50% (95% CI 32-63) efficacious against PCR-confirmed influenza. Efficacy was 42% (12 to 61) during pregnancy and 60% (36 to 75) postpartum. In women vaccinated before 29 weeks gestational age, the estimated efficacy was 30% (-2 to 52), and in women vaccinated at or after 29 weeks, efficacy was 71% (50 to 83). Efficacy was similar in infants born to mothers vaccinated before or after 29 weeks gestation (34% [95% CI 12 to 51] vs 35% [11 to 52]). There was no overall association between maternal vaccination and low birthweight, stillbirth, preterm birth, and small for gestational age. At 6 months of age, the intervention and control groups were similar in terms of underweight (weight-for-age), stunted (length-for-age), and wasted (weight-for-length). Median centile change from birth to 6 months of age was similar between the intervention and the control groups for both weight and length., Interpretation: The assessment of efficacy for women vaccinated before 29 weeks gestational age might have been underpowered, because the point estimate suggests that there might be efficacy despite wide CIs. Estimates of efficacy against PCR-confirmed influenza and safety in terms of adverse birth outcomes should be incorporated into any further consideration of maternal influenza immunisation recommendations., Funding: Bill & Melinda Gates Foundation., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Measles infection causes particularly severe disease in young children who, prior to vaccination, are dependent on maternal antibodies for protection against infection. Measles vaccination was introduced into the South African public immunization programme in 1983 and became widely available in 1992. The aim of this study was to determine measles-specific immunoglobulin G (IgG) levels in pregnant women living with and without HIV born before and after measles vaccine introduction in South Africa., Methods: Measles IgG antibody level from blood obtained at the time of delivery was compared between women who were born before 1983 (n = 349) and since 1992 (n = 349). Serum samples were tested for measles IgG antibody using an enzyme-linked immunosorbent assay. Geometric mean titres (GMTs) and the proportion with seronegative (<200 mIU/mL) or seropositive titres (≥275 mIU/mL) were compared., Results: Women born since 1992 had lower GMTs [379.7 mIU/mL (95% CI 352.7-448.6)] and fewer were seropositive (55.9%, 195/349) than women born before 1983 [905.8 mIU/mL (95% CI 784.7-1045.5); 76.8%, 268/349], for both comparisons p < 0.001., Conclusions: We found an association between measles vaccine implementation into the public immunization program in South Africa and peri-partum maternal measles immunity, where women born before vaccine introduction had higher measles IgG antibody titres and were more likely to be seropositive. These findings suggest a need to reconsider the infant measles immunization schedule in settings where women have derived immunity mainly from measles vaccine rather than wild-type virus exposure., (Copyright © 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Nasopharyngeal carriage (NPC) of Streptococcus pneumoniae is a precondition for pneumococcal disease and a source of transmission. This trial evaluated NPC of S. pneumoniae and other pathogens post-vaccination with the pneumococcal non-typeable Haemophilus influenzae (NTHi) protein D conjugate vaccine (PHiD-CV) in human immunodeficiency virus (HIV)-infected (HIV+), HIV-exposed-uninfected (HEU), and HIV-unexposed-uninfected (HUU) South African children., Methods: In this phase III, open, single-centre, controlled study (ClinicalTrials.gov: NCT00829010), 484 children were stratified by HIV status: 83 HIV+, 101 HEU, and 300 HUU. HIV+ and HEU children received a 3 + 1 PHiD-CV vaccination schedule: primary vaccination, age 6/10/14 weeks, and booster dose, age 9-10 months. HUU infants were randomised (1:1:1) to 3-dose priming and booster (HUU/3+1); 3-dose priming without booster (HUU/3+0); or 2-dose priming and booster (HUU/2+1). Bacterial NPC was assessed 8 times up to 24-27 months of age., Results: Overall pneumococcal carriage rates were similar across 3+1 groups irrespective of HIV status; trends towards higher carriage rates in the HIV+ than HEU and HUU/3+1 groups were observed at 24-27 months of age. In HUU children, carriage of any pneumococcal serotype was similar for the three different dosing schedules at all timepoints; carriage of vaccine-type pneumococci tended to be lower at 16-19 months and 24-27 months of age in children who had received a booster dose (HUU/2+1 and HUU/3+1 groups) than in the HUU/3+0 group. Carriage rates of NTHi, Staphylococcus aureus and Moraxella catarrhalis were comparable between all groups., Conclusions: HIV infection or exposure did not seem to alter the effect of PHiD-CV on pneumococcal NPC in children during their first 2 years of life. NPC prevalence of vaccine-type pneumococci following vaccination series tended to be lower in children who had received a booster dose in comparison to those who had not., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: DB, JPY, JRG, LS, NF and SS are employees of the GSK group of companies and MM was an employee of the GSK group of companies. DB, JPY, JRG, LS, MM and SS own shares of the GSK group of companies. SAM’s institution received grants from the Bill & Melinda Gates Foundation, the GSK group of companies, Novartis and Minervax and personal consulting fees for advisory boards and/or speaker’s bureaus from the GSK group of companies, Medimmune, Pfizer and Sanofi Pasteur. All other authors declare no conflict of interest., (Copyright © 2020 GlaxoSmithKline Biologicals S.A. Published by Elsevier Ltd.. All rights reserved.)

Background: Standard-dose, seasonal, trivalent, inactivated influenza vaccine induces moderate-to-low haemagglutination-inhibition antibody responses in people living with HIV. This study assessed the immunogenicity and safety of different dosing schedules of inactivated influenza vaccine in pregnant women living with HIV in South Africa., Methods: In this double-blind, randomised, controlled trial, we recruited pregnant women with HIV from seven antenatal clinics in Soweto, South Africa. Pregnant women were eligible if they were aged 18-38 years, infected with HIV, and had an estimated gestational age of 12-36 weeks. Women were randomly assigned (1:1:1), using a computer-generated randomisation list, to receive inactivated influenza vaccine containing 15 μg of each of the three seasonal influenza strains for that year, as a single dose, a double dose, or two single doses 1 month apart. Participants and study personnel were masked to group allocation. Haemagglutination-inhibition antibody responses were measured for all groups in the mothers at enrolment and at 1 month after each vaccine dose, and in the single-dose and double-dose groups within 7 days of birth in the neonates. Immunogenicity analyses only included women with visits 28-35 days apart and infants who were born at least 28 days after maternal immunisation. The primary was seroconversion rate to each of the vaccine strains in the mothers 1 month after completion of the dosing schedule, and the primary safety outcomes were frequency of local and systemic reactions. Safety was assessed in mothers and infants until 24 weeks post partum and analysed in all participants who received at least one dose of vaccine. This study is registered with ClinicalTrials.gov, NCT01527825, and is closed to accrual., Findings: Between Feb 11, and June 6, 2013, 800 pregnant women living with HIV were enrolled and randomly assigned to the single-dose (n=266), double-dose (n=265), or two-single-doses (n=269) group. In the analysable population, seroconversion rates in mothers 1 month after the final vaccine dose were significantly higher in the double-dose group (n=230; ranging from 29% to 65% for the three vaccine strains) than in the single-dose group (n=230; ranging from 18% to 49%; p≤0·019 for the three vaccine strains), but were similar between the two-single-doses group (n=220; ranging from 23% to 52%) and the single-dose group (p≥0·20 for the three vaccine strains). Safety outcomes were similar in the three groups, except for more injection-site reactions in recipients in the double-dose group., Interpretation: A regimen of double-dose inactivated influenza vaccine gave slightly greater immunogenicity than did a single-dose regimen in pregnant women living with HIV. However, immunogenicity in the double-dose group was still lower than historical data from the same setting in pregnant women without HIV. More immunogenic vaccines are needed for pregnant women living with HIV to enhance transplacental transfer of vaccine-induced protective antibodies to their newborn infants., Funding: Bill & Melinda Gates Foundation., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Rubella infection during pregnancy may cause foetal death or congenital rubella syndrome. In South Africa, the national public immunization programme does not include rubella vaccination. The aim of this study was to evaluate rubella sero-epidemiology in pregnant South African women living with and without HIV., Methods: Serum samples obtained from women living with HIV (n=552) and without HIV (n=552) were tested for rubella immunoglobulin G antibodies using an ELISA. The proportions of women with seronegative titres (<8IU/ml) and seropositive titres (≥11IU/ml), and geometric mean titres (GMT) were compared by age group and HIV status., Results: The overall proportion of rubella seropositivity was 97.8%. The proportion of seropositive women increased with age group (18-25 years: 97.0%; 26-32 years: 97.7%; 33-40 years: 99.3%; p=0.047 after adjusting for HIV status). Similar proportions of women living with and without HIV were seropositive., Conclusions: Rubella immunity was high among South African pregnant women living with and without HIV in the absence of rubella vaccination in the public immunization programme. However, a lower percentage of younger women had seropositive titres, indicating the need for routine rubella vaccination after an increase in vaccine coverage rates., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Measles morbidity and mortality rates are greatest in children <12 months old, with increased susceptibility in human immunodeficiency virus (HIV)-exposed children. We evaluated the immunogenicity and safety of an early 2-dose measles vaccine regimen administered at 6 and 12 months of age in South Africa., Methods: HIV-unexposed (HU) (n = 212) and HIV-exposed, uninfected (HEU) (n = 71) children received measles vaccination (CAM-70) at 6 and 12 months of age. Measles immunoglobulin G titers were measured by means of enzyme-linked immunosorbent assay before and 1 month after each vaccine dose., Results: The majority of children (88.2% HU and 95.8% HEU; P = .04) were seronegative (<150 mIU/mL) to measles at 4.2 months of age. This was particularly evident among infants of mothers born from 1992 onwards (year of public nationwide measles vaccine availability). One month after the first measles vaccine, 42.3% of HU and 46.4% of HEU children were seropositive (≥330 mIU/mL). After the second dose, the proportion seropositive increased to 99.0% in HU and 95.3% in HEU children. Safety profiles were similar between HU and HEU children., Conclusions: Early 2-dose measles vaccination at 6 and 12 months of age was safe and induced antibody responses in HU and HEU children, which could partly offset the early loss of maternally derived antibodies in infants born to predominantly measles-vaccinated mothers., Clinical Trials Registration: NCT03330171., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Iron acquisition is critical for life. Ferroportin (FPN) exports iron from mature erythrocytes, and deletion of the Fpn gene results in hemolytic anemia and increased fatality in malaria-infected mice. The FPN Q248H mutation (glutamine to histidine at position 248) renders FPN partially resistant to hepcidin-induced degradation and was associated with protection from malaria in human studies of limited size. Using data from cohorts including over 18,000 African children, we show that the Q248H mutation is associated with modest protection against anemia, hemolysis, and iron deficiency, but we found little evidence of protection against severe malaria or bacteremia. We additionally observed no excess Plasmodium growth in Q248H erythrocytes ex vivo, nor evidence of selection driven by malaria exposure, suggesting that the Q248H mutation does not protect from malaria and is unlikely to deprive malaria parasites of iron essential for their growth.

Introduction: The purpose of this study was to evaluate the association of influenza vaccine during pregnancy and adverse fetal outcomes. Preventing fetal death, low birth weight, small for gestational age birth and preterm birth are important potential effects of antenatal maternal influenza immunization for which there are conflicting data., Materials and Methods: A double-blind, randomized, placebo-controlled clinical trial of trivalent inactivated influenza vaccine was conducted in South Africa from March 2011 until after the 2012 influenza season when the infants born had reached the age of 24 weeks. Mothers were administered the vaccine or placebo during pregnancy at a gestation of 20 to 36 weeks. A comparison of rates of fetal death, low birth weight, small for gestational age birth, and preterm birth, between vaccinated and placebo groups was made. Fetal outcome differences between the groups were measured using Student's t-tests, vaccine efficacy with 95% confidence intervals, and Poisson regression for incidence rates. All analyses except fetal death excluded mothers who were administered vaccine or placebo after 34 weeks gestational age., Results: There were 2116 HIV-uninfected pregnant women age 18 to 38 years in the trial; 2005 infants were born to mothers where vaccine or placebo had been administered ≥ 14 days prior to delivery, and there were 6 miscarriages and 23 stillbirths. There was no significant vaccine efficacy (with [95% confidence interval]) on fetal death (-21.2% [-150.8, 41.4]), low birth weight (-11.1% [-42.3, 12.5]), small for gestational age birth (-9.9% [-35.6, 11.0]), or preterm birth (-21.3% [-60.5, 8.3]). Neither was vaccine efficacy demonstrated when the analysis was restricted to infants of mothers who were exposed to an influenza season (1832 outcomes available)., Conclusion: We did not find a beneficial effect of trivalent inactivated influenza vaccine during pregnancy on adverse fetal outcomes., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Human immunodeficiency virus (HIV)-exposed, uninfected infants have higher risks of respiratory syncytial virus-associated hospitalization than HIV-unexposed infants. Despite similar neutralizing antibody titers between HIV-infected and -uninfected women, maternal HIV infection and hypergammaglobulinemia were independently associated with lower titers in newborns. Maternal hypergammaglobulinemia was associated with lower cord-to-maternal antibody ratio., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: A globally standardized approach in high and low and middle-income countries (LMIC) to actively monitor the safety of vaccines for pregnant women during development and implementation phases is critical. Brighton Collaboration's (BC) Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA) project has developed globally standardized case definitions (CDs) of key obstetric and neonatal terms for the assessment of safety of vaccines in pregnancy. CDs are categorized into levels of diagnostic certainty, facilitating their use in varied settings. This study evaluates the field performance of CDs in LMIC., Methods: Data from pregnant participants of RCTs for trivalent inactivated influenza vaccine conducted at Chris Hani Baragwanath Academic Hospital, South Africa (SA) between 2011 and 2013 were reviewed retrospectively for preterm birth, stillbirth and hypertension CDs and the Gestational age assessment (GA) algorithm. Data from an ongoing pneumococcal vaccine trial (conducted at MRC Unit, The Gambia) were collected prospectively for GA., Results: For GA, 600 mother-infant dyads from Gambia and 155 mother-infant dyads from SA were reviewed. Level 2B (unsure LMP and US in 2nd trimester) was the most common level seen in Gambia (63%) and level 3B1 (unsure LMP with physical examination) in SA (43%). Preterm deliveries had similar results in SA. The pregnancy-induced hypertension definition performed well, with 96% (54/56) of cases fulfilling 'level 1' for 'preeclampsia with severe features'. 24 stillbirths were identified and 21 records were reviewed; 73.3% (11/15) of the stillbirths classified as antepartum by attending physicians and 83.3% (5/6) of the intrapartum stillbirths did not fulfil the criteria for any level of certainty., Conclusion: BC CDs for neonatal and maternal outcomes (preterm and hypertension) and GA were sensitive, reliable and feasible to use in RCTs in SA and Gambia. Modifications to the stillbirth CD are required to improve its usefulness in varied settings., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: About 2·6 million third-trimester stillbirths occur annually worldwide, mostly in low-income and middle-income countries, where the causes of these deaths are rarely investigated., Methods: We did a prospective, hospital-based, observational study in Soweto, South Africa, to investigate the causes of stillbirths in fetuses of at least 22 weeks' gestational age or with a birthweight of at least 500 g. Maternal clinical information was abstracted from medical records. Investigations included placental macroscopic and histopathological examination and fetal blood culture (including screening for pathogenic bacteria associated with stillbirth). Cases missing one or more of these investigations were considered to have incomplete samples and were excluded from the analysis of cause of stillbirth. Causes of stillbirths were assessed by individual case reviews by at least two obstetricians, and classified with a modified Stillbirth Collaborative Research Network classification system., Findings: Between Oct 9, 2014, and Nov 8, 2015, we enrolled 354 stillbirths (born to 350 women). Among the women with available data, 133 (38%) of 350 had hypertension, median age was 27 years (IQR 23-33), 51 (18%) of 291 were obese, six (2%) of 344 had syphilis, and 94 (27%) of 350 had HIV. 63 (18%) of 341 fetuses showed intrauterine growth restriction. Of 298 cases (born to 294 mothers) with complete samples, the most common causes of stillbirth were maternal medical conditions (64 [21%] cases; among them 56 [19%] with hypertensive disorders and six [2%] with diabetes), placental or fetal infections (58 [19%]; 47 [16%] with fetal invasive bacterial infection), pathological placental conditions (57 [19%]; among them 27 [9%] with fetal membrane and placental inflammation and 26 [9%] with circulatory abnormalities), and clinical obstetric complications (54 [18%]; 45 [15%] with placental abruption). Six (2%) stillbirths were attributed to fetal, genetic, or structural abnormalities. In 55 (18%) cases, no cause of death was identified. The most common bacteria to which stillbirths due to fetal invasive infections were attributed were group B streptococcus (15 [5%] cases), E coli (12 [4%]), E faecalis (six [2%]), and S aureus (five [2%])., Interpretation: Targeted investigation of stillbirths (even without fetal autopsy) can ascertain a cause of stillbirth in most cases. Further studies using such investigations are needed to inform the prioritisation of interventions to reduce stillbirths globally., Funding: Novartis and GlaxoSmithKline., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: We previously reported that despite HIV-infected pregnant women had modest humoral immune responses to inactivated influenza vaccine (IIV) measured by hemagglutination-inhibition (HAI) assay, the observed vaccine efficacy against influenza disease was higher than predicted by HAI; suggesting that IIV may confer protection to HIV-infected individuals by additional mechanisms. We evaluated the response to IIV by microneutralization (MN) and HAI assays and correlated both methods in HIV-infected and HIV-uninfected pregnant women., Methods: MN and HAI antibodies were measured pre-vaccination and approximately one-month post-vaccination in 80 HIV-infected and 75 HIV-uninfected women who received IIV. Geometric mean titers (GMTs), fold-change in titers and seroconversion rates were determined for the three influenza stains in the vaccine., Results: After vaccination there were significant increases in MN and HAI GMTs for the three vaccine strains in both HIV-infected and HIV-uninfected women. HIV-infected women had, however, a lower immune response compared to HIV-uninfected. Fold-increases were 2 to 3-times higher for MN assay compared to HAI assay for the influenza-A strains. Also a higher percentage of women seroconverted by MN than by HAI assay for the influenza-A strains. There was high positive correlation between MN and HAI assays, except for the B/Victoria strain at pre-vaccination., Conclusions: In general, the MN assay was more sensitive than the HAI assay. Microneutralization antibodies might correlate better with protection against influenza infection., Competing Interests: The authors have declared that no competing interests exist.

Background: Limited data exist on the burden of respiratory syncytial virus (RSV) illness among pregnant women, to determine their potential benefit from RSV vaccination. We evaluated the incidence of RSV illness from midpregnancy until 24 weeks postpartum in human immunodeficiency virus (HIV)-uninfected and HIV-infected women and their infants., Methods: Mother-infant dyads were enrolled in maternal influenza vaccine efficacy trials. These included 1060 and 1056 HIV-uninfected pregnant women in 2011 and 2012, respectively, 194 HIV-infected pregnant women in 2011, and their infants. Upper respiratory tract samples obtained at illness visits were tested for RSV., Results: The incidence (per 1000 person-months) of RSV illness (n = 43 overall) among HIV-uninfected women was lower in 2011 (1.2; 95% confidence interval [CI], .6-2.2) than in 2012 (4.0; 95% CI, 2.8-5.6). The incidence of RSV illness (n = 5) in HIV-infected women was 3.4 (95% CI, 1.4-8.1). Maternal RSV infection was associated with respiratory symptoms including cough (72.1%), rhinorrhea (39.5%), sore throat (37.2%), and headache (42%), but fever was absent. RSV infection during pregnancy was not associated with adverse pregnancy outcomes. Postpartum, RSV infection in mothers (n = 27) was associated with concurrent infection among 51.9% of their infants and, conversely, 29.8% of mothers investigated within 7 days of their infants having an RSV illness also tested positive for RSV., Conclusions: RSV infection is associated with respiratory illness during pregnancy and postpartum. Vaccination of pregnant women against RSV could benefit the mother, albeit primarily against nonfebrile illness, and her infant., Clinical Trial Registration: NCT01306669 and NCT01306682.

Background: We evaluated the immunogenicity and safety of 1 and 2 doses of quadrivalent meningococcal serogroup A, C, W and Y tetanus toxoid-conjugate vaccine (MenACWY-TT) given alone or co-administered with 13-valent pneumococcal conjugate vaccine (PCV13) in toddlers., Methods: In this phase III, open-label, controlled, multicentre study (NCT01939158), healthy toddlers aged 12-14 months were randomised into 4 groups to receive 1 dose of MenACWY-TT at month (M) 0 (ACWY&#95;1), 2 doses of MenACWY-TT at M0 and M2 (ACWY&#95;2), MenACWY-TT and PCV13 at M0 (Co-ad), or PCV13 at M0 and MenACWY-TT at M2 (PCV13/ACWY). Immune responses were assessed 1 month post-each vaccination. Solicited and unsolicited symptoms were recorded for 4 and 31 days post-each vaccination, respectively; serious adverse events (SAEs) and new onset of chronic illnesses (NOCIs) up to M9 from first vaccination., Results: 802 toddlers were vaccinated. Post-dose 1 of MenACWY-TT, ≥92.8% of toddlers had rSBA titres ≥1:8, and ≥62.5% had hSBA titres ≥1:4 for each meningococcal serogroup. Post-dose 2 of MenACWY-TT, rSBA titres ≥1:8 were observed in ≥98.0% and hSBA titres ≥1:4 in ≥95.3% of toddlers. Percentages of toddlers with hSBA titres ≥1:4 were higher after 2 doses versus 1 dose of MenACWY-TT for MenW (97.1% versus 62.5-68.9%) and MenY (95.3% versus 64.3-67.6%). Non-inferiority of immune responses to co-administered MenACWY-TT and PCV13 over their separate administration was demonstrated. AEs incidence was comparable among groups. SAEs were reported for 4.9%, 5.1%, 5.5% and 7.5%, and NOCIs for 2.0%, 3.0%, 0.5% and 3.5% of toddlers in the ACWY&#95;1, ACWY&#95;2, Co-ad and PCV13/ACWY groups, respectively; 4 SAEs reported in 3 toddlers were vaccine-related. Two fatal vaccine-unrelated SAEs were reported., Conclusion: MenACWY-TT was immunogenic when administered as a single dose at 12-14 months of age. A second dose in toddlers increased hSBA responses against MenW and MenY. MenACWY-TT and PCV13 can be co-administered without impairing the immunogenicity or safety profile of either vaccine., (Copyright © 2018 GlaxoSmithKline Biologicals SA. Published by Elsevier Ltd.. All rights reserved.)