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Respiratory syncytial virus (RSV) is the most important viral cause of pneumonia in early childhood (ie, younger than 2 years), responsible for high infant morbidity and mortality worldwide. It is widely accepted that an effective vaccine against RSV would have a major impact on child health globally. Despite the setbacks of the clinical trials in the 1960s, there has been a recent and significant revival of interest in vaccines against RSV, with several promising candidates undergoing evaluation. In this Review, we describe the epidemiological and immunological background to RSV infection and subsequently focus on the promising pipeline of RSV vaccine development. We discuss the potential for implementation of a safe and immunogenic RSV vaccine within the context of global health and with regards to a range of strategies, including vaccination of women during pregnancy, which is likely to emerge as a beneficial and feasible public health tool. This approach would provide interim protection to vulnerable, RSV-naive infants and other high risk groups, in which the burden of admission to hospital and death is greatest. Extending research and implementation from resource-rich to resource-poor settings is required to enhance our understanding of RSV immunity and inform vaccine development and delivery strategies for all settings. We summarise key outstanding issues for researchers and policy makers to understand the interplay of biological and non-biological factors affecting design and distribution of a successful RSV vaccine globally.

The COVID-19 pandemic response has caused disruption to healthcare services globally, including to routine immunizations. To understand immunization service interruptions specifically for maternal, neonatal and infant vaccines, we captured the local experiences of members of the Immunising Pregnant Women and Infants Network (IMPRINT) by conducting an online survey over 2-weeks in April 2020. IMPRINT is a global network of clinicians and scientists working in maternal and neonatal vaccinology. The survey included discrete questions to quantify the extent of disruption as well as free-text options to explore the reasons behind reported disruptions. Of the 48 responses received, the majority (75%) were from low-and-middle-income countries (LMICs). Of all respondents, 50% or more reported issues with vaccine delivery within their country. Thematic analysis identified three key themes behind immunization disruption: “access” issues, e.g., logistical barriers, “provider” issues, e.g., staff shortages and user “concern” about attending immunization appointments due to COVID-19 fear. Access and provider issues were more commonly reported by LMIC respondents. Overall, respondents reported uncertainty among parents and healthcare providers regarding routine immunization. We conclude that further quantification of routine vaccination disruption is needed, alongside health service prioritization, logistical support and targeted communication strategies to reinforce routine immunizations during the COVID-19 response.

Pertussis (‘whooping cough’) is a severe respiratory tract infection that primarily affects young children and unimmunised infants. Despite widespread vaccine coverage, it remains one of the least well-controlled vaccine-preventable diseases, with a recent resurgence even in highly vaccinated populations. Although the exact underlying reasons are still not clear, emerging evidence suggests that a key factor is the replacement of the whole-cell (wP) by the acellular pertussis (aP) vaccine, which is less reactogenic but may induce suboptimal and waning immunity. Differences between vaccines are hypothesised to be cell-mediated, with polarisation of Th1/Th2/Th17 responses determined by the composition of the pertussis vaccine given in infancy. Moreover, aP vaccines elicit strong antibody responses but fail to protect against nasal colonisation and/or transmission, in animal models, thereby potentially leading to inadequate herd immunity. Our review summarises current knowledge on vaccine-induced cellular immune responses, based on mucosal and systemic data collected within experimental animal and human vaccine studies. In addition, we describe key factors that may influence cell-mediated immunity and how antigen-specific responses are measured quantitatively and qualitatively, at both cellular and molecular levels. Finally, we discuss how we can harness this emerging knowledge and novel tools to inform the design and testing of the next generation of improved infant pertussis vaccines.

Sensitive serological testing is essential to estimate the proportion of the population exposed or infected with SARS-CoV-2, to guide booster vaccination and to select patients for treatment with anti-SARS-CoV-2 antibodies. The performance of serological tests is usually evaluated at 14–21 days post infection. This approach fails to take account of the important effect of time on test performance after infection or exposure has occurred. We performed parallel serological testing using 4 widely used assays (a multiplexed SARS-CoV-2 Nucleoprotein (N), Spike (S) and Receptor Binding Domain assay from Meso Scale Discovery (MSD), the Roche Elecsys-Nucleoprotein (Roche-N) and Spike (Roche-S) assays and the Abbott Nucleoprotein assay (Abbott-N) on serial positive monthly samples collected as part of the Co-STARs study ( www.clinicaltrials.gov , NCT04380896) up to 200 days following infection. Our findings demonstrate the considerable effect of time since symptom onset on the diagnostic sensitivity of different assays. Using a time-to-event analysis, we demonstrated that 50% of the Abbott nucleoprotein assays will give a negative result after 175 days (median survival time 95% CI 168–185 days), compared to the better performance over time of the Roche Elecsys nucleoprotein assay (93% survival probability at 200 days, 95% CI 88–97%). Assays targeting the spike protein showed a lower decline over the follow-up period, both for the MSD spike assay (97% survival probability at 200 days, 95% CI 95–99%) and the Roche Elecsys spike assay (95% survival probability at 200 days, 95% CI 93–97%). The best performing quantitative Roche Elecsys Spike assay showed no evidence of waning Spike antibody titers over the 200-day time course of the study. We have shown that compared to other assays evaluated, the Abbott-N assay fails to detect SARS-CoV-2 antibodies as time passes since infection. In contrast the Roche Elecsys Spike Assay and the MSD assay maintained a high sensitivity for the 200-day duration of the study. These limitations of the Abbott assay should be considered when quantifying the immune correlates of protection or the need for SARS-CoV-2 antibody therapy. The high levels of maintained detectable neutralizing spike antibody titers identified by the quantitative Roche Elecsys assay is encouraging and provides further evidence in support of long-lasting SARS-CoV-2 protection following natural infection.

Immunisation of the newborn represents a key global strategy in overcoming morbidity and mortality due to infection in early life. Potential limitations, however, include poor immunogenicity, safety concerns and the development of tolerogenicity or hypo-responsiveness to either the same antigen and/or concomitant antigens administered at birth or in the subsequent months. Furthermore, the neonatal immunological milieu is polarised towards Th2-type immunity with dampening of Th1-type responses and impaired humoral immunity, resulting in qualitatively and quantitatively poorer antibody responses compared to older infants. Innate immunity also shows functional deficiency in antigen-presenting cells: the expression and signalling of Toll-like receptors undergo maturational changes associated with distinct functional responses. Nevertheless, the effectiveness of BCG, hepatitis B and oral polio vaccines, the only immunisations currently in use in the neonatal period, is proof of concept that vaccines can be successfully administered to the newborn via different routes of delivery to induce a range of protective mechanisms for three different diseases. In this review paper, we discuss the rationale for and challenges to neonatal immunisation, summarising progress made in the field, including lessons learnt from newborn vaccines in the pipeline. Furthermore, we explore important maternal, infant and environmental co-factors that may impede the success of current and future neonatal immunisation strategies. A variety of approaches have been proposed to overcome the inherent regulatory constraints of the newborn innate and adaptive immune system, including alternative routes of delivery, novel vaccine configurations, improved innate receptor agonists and optimised antigen-adjuvant combinations. Crucially, a dual strategy may be employed whereby immunisation at birth is used to prime the immune system in order to improve immunogenicity to subsequent homologous or heterologous boosters in later infancy. Similarly, potent non-specific immunomodulatory effects may be elicited when challenged with unrelated antigens, with the potential to reduce the overall risk of infection and allergic disease in early life.

The study aimed to assess the relationship between clinical features, routine laboratory parameters, including conventional blood culture, and identification of microorganisms by a commercial system of Polymerase Chain Reaction coupled with Electrospray Ionization Mass Spectrometry (PCR/ESI-MS) (Abbot Iridica) in infants with suspected early-onset infection. Prospective observational cohort study. Neonatal intensive care unit and postnatal ward at a tertiary hospital within an urban setting. Neonates >=34 weeks gestation with clinically suspected early-onset infection between January 2016 and March 2017 were recruited. Blood samples were taken at the time of suspected infection for both blood culture inoculation (BacT/ALERT system) and PCR/ESI-MS analysis (0.5ml). An electronic database was used to document demographic and clinical details. 54 infants were studied with a median (IQR) gestational age and birth weight of 39.7 (37.5-41.0) weeks and 3.2 (2.7-3.5) kg respectively. 1 infant had both bacterial DNA detected on PCR/ESI-MS and bacterial growth on blood culture (Group B ). 9 infants had bacterial DNA detected but with negative blood culture. The bacteria identified were sp ,. All infants with no bacterial DNA detected on PCR/ESI-MS also had a negative blood culture result. Infants with positive bacterial DNA identification in blood had significantly higher CRP values; initially (p=0.002), when repeated after 18-24 hours (p=0.02) and maximally within the first 72 hours (p=0.03). The proportion of infants with a CRP> 5 mg/L was significantly higher if bacterial DNA had been detected (p=0.01). PCR/ESI-MS detected bacterial DNA of organisms considered pathogenic in four times more blood samples than culture alone, and had a high sensitivity and negative predictive value. Bacterial DNA was detected by PCR/ESI-MS in infants who did not have bacterial growth on blood culture and this was associated with a raised inflammatory marker. It may be a useful tool to exclude sepsis in the neonatal cohort and reassess the need for prolonged antibiotic treatment. The results are promising but there is a need to improve blood collection methods to take advantage of the potential benefits of molecular detection.

Background The reported number of SARS-CoV-2 cases and deaths are lower in Africa compared to many high-income countries. However, in African cohorts, detailed characterisation of SARS-CoV-2 mucosal and T cell immunity are limited. We assessed the SARS-CoV-2-specific immune landscape in The Gambia during the presence of the pre-Delta variant in July 2021. Methods A cross-sectional assessment of SARS-CoV-2 immunity in 349 unvaccinated individuals from 52 Gambian households was performed between March–June 2021. SARS-CoV-2 spike (S) and nucleocapsid (N) specific binding antibodies were measured by ELISA, variant-specific serum neutralizing-antibodies (NAb) by viral pseudotype assays and nasal fluid IgA by mesoscale discovery assay. SARS-CoV-2 T-cell responses were evaluated using ELISpot assay. Results We show that adjusted anti-Spike antibody seroprevalence is 56.7% (95% confidence interval (CI) 49.0-64.0), with lower rates in children <5 years (26.2%, 13.9-43.8) and 5-17 years (46.4%, 36.2-56.7) compared to adults 18-49 years (78.4%, 68.8–85.8). Among spike-seropositive individuals, NAb titres are highest against Alpha variant (median IC50 110), with 27% showing pre-existing Delta variant titres >1:50. T-cell responses are higher in spike-seropositive individuals, although 34% of spike-seronegative individuals show responses to at least one antigen pool. We observe strong correlations within SARS-CoV-2 T-cell, mucosal IgA, and serum NAb responses. Conclusions High SARS-CoV-2 seroprevalence in The-Gambia induce mucosal and blood immunity, reducing Delta and Omicron impact. Children are relatively protected from infection. T-cell responses in seronegative individuals may indicate either pre-pandemic cross-reactivity or individuals with a T-cell dominated response to SARS-CoV-2 infection with absent or poor humoral responses. Plain language summary The COVID-19 pandemic caused many illnesses and deaths worldwide. In Africa, the reported number of COVID-19 cases remained low and while under-reporting may have played a role, no increase in deaths was seen in The Gambia during the first year of the COVID-19 pandemic. There is limited data on how the immune system of Africans respond to COVID-19 infections. Our aim was to assess COVID-19 immune responses using blood and nasal swabs collected from the participants. Measurement of immune cell function and antibody levels, showed that COVID-19 infection activated different specialized cells of the immune system, including certain white blood cells (T cells) and antibodies. Antibodies are proteins made by the cells in our body, found in the blood and mucous membranes and protect against infection. We also found that COVID-19 infection rates were higher in adults compared to children and that the immune responses from an infection with earlier COVID-19 variants may have conferred protection against infection with later variants. These findings contribute to our understanding of how Africans of different ages responded to COVID-19 infection. Jagne, Jobe et al. assess the SARS-CoV-2-specific immune landscape of people in The Gambia exposed to the pre-Delta variant in July 2021. SARS-CoV-2 infection induces T cell, mucosal, and systemic antibody responses, with variations observed across these immune compartments.

Clinical findings were consistent with Henoch-Schönlein purpura (HSP) and he was discharged with community follow-up to monitor his lesions, blood pressure and urinalysis. Learning points The differential diagnosis of necrotic cutaneous lesions in children includes local or systemic infection, thromboembolic disease, Henoch-Schönlein purpura (HSP), polyarteritis nodosa, antineutrophil cytoplasmic antibodies-associated vasculitis and purpura fulminans.1 Cutaneous manifestations of HSP are typically benign and self-limiting, although they can be associated with significant morbidity in severe cases. Introduction of immunosuppression may be necessary to control the inflammation and limit the extent of skin necrosis.2 The factors contributing to necrotic complications of HSP in individual patients remain unclear. Inherited thrombophilia tendencies should be considered and explored further in these cases.3 Contributors Data collection and analysis was performed by SD and AS.

Vaccines recommended in pregnancy against pertussis, tetanus, or influenza, or all, are established tools to protect not only pregnant women, but also infants during the vulnerable postnatal period.3 Although country-specific data are emerging that show that maternal vaccine uptake declined in 2020,4 to date, no similar global estimates of COVID-19-related disruptions to these services have been published. The IMmunising PRegnant women and INfants neTwork (IMPRINT), a global, interdisciplinary collaboration of key stakeholders in maternal and infant vaccinology, captured the grassroots experiences of changes to vaccine delivery among our network members by an initial online survey in April, 2020.5 We reported issues from 18 countries across five continents related to service access (eg, logistical barriers) and provision (eg, staff shortages), as well as user concerns over attending appointments.5 1 year on, in May, 2021, we repeated this survey, and it is evident that routine maternal and infant vaccination programmes are yet to fully recover, despite the local or national measures, or both, implemented to mitigate disruption. Efficiency and safety of maternity services need to be prioritised, with clearer communication to women on potential risks as well as any specific safety measures implemented.6 Pregnant women are also at risk of severe outcomes from COVID-19.7 Promoting and delivering COVID-19 immunisation itself in pregnancy, already recommended in many countries, not only confers protection8 but might be one effective strategy to mitigate the current interruptions to antenatal vaccination programmes.3 Lakruwan Wanniarachchi/Getty Images All authors are members of IMPRINT, which is funded by UK Research and Innovation and the Global Challenges Research Fund.

Vaccinating women against pertussis in pregnancy protects young infants from severe disease and death. Vaccination-induced maternally derived antibodies, however, might subsequently modulate (and specifically blunt) the infant's serological response to their primary series of pertussis vaccinations. We examined the effect of pertussis immunisation in pregnancy on the immunogenicity of primary acellular or whole-cell pertussis vaccines in a west African cohort. GaPs was a randomised, controlled, double-blind, phase 4 trial conducted in The Gambia. We used a predefined block randomisation scheme to randomly assign healthy, HIV-negative, pregnant participants (1:1) to receive a pertussis-containing (tetanus-diphtheria-acellular pertussis-inactivated polio virus [Tdap-IPV]) or tetanus-toxoid only vaccine at 28–34 weeks' gestation. At the same time, their infants were randomly assigned (1:1) to receive diphtheria-tetanus-acellular pertussis (DTaP) or diphtheria-tetanus-whole-cell pertussis (DTwP) primary vaccine at 8, 12, and 16 weeks postnatally. Participants and trial staff were masked to the allocation of the maternal vaccine. The field team and participants became unmasked to the allocation of the infant vaccine at 16 weeks; laboratory staff and all other investigators remained masked to infant vaccine allocation until the end of the trial. The primary outcome was geometric mean concentration (GMC) of infant pertussis toxin-specific antibodies at 20 weeks and 9 months postnatally and was assessed in infants who received all three doses of the primary vaccine. Secondary outcomes included memory B-cell responses, and exploratory outcomes were total pertussis-specific antibody binding concentrations and functional antibody titres (pertussis toxin-specific neutralising activity [PTNA] and serum bactericidal activity [SBA]). Vaccine reactogenicity was assessed in mothers and infants for 3 days after each vaccine dose. Pregnant women had an extra safety visit 7 days after vaccination. The study is registered with ClinicalTrials.gov, NCT03606096. Between Feb 13, 2019, and May 17, 2021, we enrolled 343 maternal–infant pairs. 239 (77%) infants were included in the per-protocol immunogenicity analysis. Among infants of mothers receiving Tdap-IPV in pregnancy, at 20 weeks postnatally, the GMCs of anti-pertussis toxin IgG were more than three-fold lower in infants vaccinated with three doses of DTwP (n=64) than in infants vaccinated with three doses of DTaP (n=53; adjusted geometric mean ratio 0·28, 98·75% CI 0·16–0·50). This difference persisted up to 9 months (0·31, 0·17–0·55). Conversely, among infants born to tetanus toxoid-immunised mothers, post-vaccination GMCs of anti-pertussis toxin IgG at 9 months were higher in those vaccinated with DTwP (n=58) than in those vaccinated with DTaP (n=64; 2·02, 1·15–3·55). Tdap-IPV immunisation in pregnancy blunted anti-pertussis toxin IgG following primary vaccination in all infants but particularly in those receiving DTwP, with GMCs of anti-pertussis toxin IgG more than eight-fold lower in DTwP-vaccinated infants born to Tdap-IPV-vaccinated mothers than in DTwP-vaccinated infants born to tetanus toxoid-immunised mothers (0·12, 98·75% CI 0·07–0·22 at 20 weeks; 0·07, 0·03–0·17 at 9 months). Similarly, DTwP-vaccinated infants born to Tdap-IPV-vaccinated mothers also showed significant blunting of PTNA, SBA, total pertussis-specific antibody binding, and memory B-cell responses after primary immunisation, whereas minimal blunting was observed among DTaP-vaccinated infants. However, the absolute levels of these responses generated by DTwP-vaccinated infants remained similar to or, in many cases, were higher than those generated by DTaP-vaccinated infants. There was no difference in reactogenicity between the two maternal vaccines, with most reactions graded 0 or 1. There were no serious adverse events related to vaccination or trial participation. Vaccinating women with Tdap-IPV in pregnancy was safe and well tolerated in a sub-Saharan African setting and boosted the quantity and quality of pertussis-specific antibodies in infants in early life. Although Tdap-IPV was associated with relative blunting of the immune response to the DTwP primary vaccination series, pertussis-specific antibody quality and memory B-cell responses were nevertheless preserved, regardless of the vaccine given during pregnancy. GaPs was conducted as part of the Pertussis Correlates Of Protection Europe (PERISCOPE) consortium, which received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement 115910. This Joint Undertaking receives support from the EU's Horizon 2020 research and innovation programme, the European Federation of Pharmaceutical Industries and Associations, and the Bill & Melinda Gates Foundation.