Imperial College London

Dr. Beth Holder

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Senior Lecturer in Maternal and Fetal Health
 
 
 
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Contact

 

+44 (0)20 7594 1773b.holder Website

 
 
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Location

 

3 008Institute of Reproductive and Developmental BiologyHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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70 results found

Timms K, Holder B, Day A, Mclaughlin J, Forbes KA, Westwood Met al., 2022, Watermelon-derived extracellular vesicles influence human ex vivo placental cell behavior by altering intestinal secretions, Molecular Nutrition and Food Research, Vol: 66, Pages: 1-12, ISSN: 1613-4125

ScopeDuring pregnancy, mother-to-fetus transfer of nutrients is mediated by the placenta; sub-optimal placental development and/or function results in fetal growth restriction (FGR), and the attendant risk of stillbirth, neurodevelopmental delay, and non-communicable diseases in adulthood. A maternal diet high in fruit and vegetables lowers the risk of FGR but the association cannot be explained fully by known macro- and micronutrients.Methods and resultsThis study investigates if dietary-derived extracellular vesicles (EVs) can regulate placental function. The study characterizes the microRNA and protein cargo of EVs isolated from watermelon, show they are actively internalized by human intestinal epithelial cells in vitro, use mass spectrometry to demonstrate that they alter the intestinal secretome and bioinformatic analyses to predict the likely affected pathways in cells/tissues distal to gut. Application of the watermelon EV-modified intestinal secretome to human placental trophoblast cells and ex vivo tissue explants affects the trophoblast proteome and key aspects of trophoblast behavior, including migration and syncytialization.ConclusionDietary-derived plant EVs can modify intestinal communication with distal tissues, including the placenta. Harnessing the beneficial properties of dietary-derived plant EVs and/or exploiting their potential as natural delivery agents may provide new ways to improve placental function and reduce rates of FGR.

Journal article

Skirrow H, Barnett S, Bell S, Mounier-Jack S, Kampmann B, Holder Bet al., 2022, Women's views and experiences of accessing pertussis vaccination in pregnancy and infant vaccinations during the COVID-19 pandemic: A multi-methods study in the UK, Vaccine, Vol: 40, Pages: 4942-4954, ISSN: 0264-410X

BackgroundCOVID-19 changed access to healthcare, including vaccinations, in the United Kingdom (UK). This study explored UK women’s experiences of accessing pertussis vaccination during pregnancy and infant vaccinations during COVID-19.MethodsAn online cross-sectional survey was completed, between 3rd August-11th October 2020, by 1404 women aged 16+ years who were pregnant at some point after the first UK lockdown from March 23rd, 2020. Ten follow-up semi-structured interviews were conducted.ResultsMost women surveyed were pregnant (65.7%) and a third postnatal (34.3%). Almost all women (95.6%) were aware that pertussis vaccination is recommended in pregnancy. Most pregnant (72.1%) and postnatal women (84.0%) had received pertussis vaccination; however, access issues were reported.Over a third (39.6%) of women had a pregnancy vaccination appointment changed. COVID-19 made it physically difficult to access pregnancy vaccinations for one fifth (21.5%) of women and physically difficult to access infant vaccinations for almost half of women (45.8%). Nearly half of women (45.2%) reported feeling less safe attending pregnancy vaccinations and over three quarters (76.3%) less safe attending infant vaccinations due to COVID-19. The majority (94.2%) felt it was important to get their baby vaccinated during COVID-19.Pregnant women from ethnic-minorities and lower-income households were less likely to have been vaccinated. Minority-ethnicity women were more likely to report access problems and feeling less safe attending vaccinations for both themselves and their babies.Qualitative analysis found women experienced difficulties accessing antenatal care and relied on knowledge from previous pregnancies to access vaccines in pregnancy.ConclusionDuring the ongoing and future pandemics, healthcare services should prioritise equitable access to routine vaccinations, including tailoring services for ethnic-minority families who experience greater barriers to vaccination.

Journal article

Maertens K, Leuridan E, Munoz FM, Zimmermann P, Curtis N, Halperin S, Rots N, Barug D, Holder B, Sadarangani M, Abu-Raya Bet al., 2022, Impact of vaccination during pregnancy on infants' immune responses to vaccinations- definitions and statistical approaches., Vaccine, Vol: 40, Pages: 4292-4295

Journal article

Taylor SA, Sharma S, Remmel CAL, Holder B, Jones CE, Marchant A, Ackerman MEet al., 2022, HIV-Associated Alterations of the Biophysical Features of Maternal Antibodies Correlate With Their Reduced Transfer Across the Placenta, JOURNAL OF INFECTIOUS DISEASES, Vol: 226, Pages: 1441-1450, ISSN: 0022-1899

Journal article

Pantazi P, Kaforou M, Guller S, Tang Z, Clements T, Holder Bet al., 2022, CHARACTERIZATION OF EXTRACELLULAR VESICLES FROM PLACENTAL MACROPHAGES (HOFBAUER CELLS) IN NORMAL PHYSIOLOGY AND INFECTION, Publisher: W B SAUNDERS CO LTD, Pages: E76-E76, ISSN: 0143-4004

Conference paper

Fakonti G, Pantazi P, Bokun V, Holder Bet al., 2022, Placental macrophage (Hofbauer cell) responses to infection during pregnancy: a systematic scoping review, Frontiers in Immunology, Vol: 12, Pages: 1-20, ISSN: 1664-3224

Background: Congenital infection of the fetus via trans-placental passage of pathogens can result in severe morbidity and mortality. Even without transmission to the fetus, infection of the placenta itself is associated with pregnancy complications including pregnancy loss and preterm birth. Placental macrophages, also termed Hofbauer cells (HBCs), are fetal-origin macrophages residing in the placenta that are likely involved in responding to placental infection and protection of the developing fetus. As HBCs are the only immune cell present in the villous placenta, they represent one of the final opportunities for control of infection and prevention of passage to the developing fetus.Objective and Rationale: The objective of this review was to provide a systematic overview of the literature regarding HBC responses during infection in pregnancy, including responses to viral, bacterial, and parasitic pathogens.Methods: PubMed and Scopus were searched on May 20th, 2021, with no limit on publication date, to identify all papers that have studied placental macrophages/Hofbauer cells in the context of infection. The following search strategy was utilized: (hofbauer* OR “hofbauer cells” OR “hofbauer cell” OR “placental macrophage” OR “placental macrophages”) AND [infect* OR virus OR viral OR bacteri* OR parasite* OR pathogen* OR LPS OR “poly(i:c)” OR toxoplasm* OR microb* OR HIV)].Outcomes: 86 studies were identified for review. This included those that investigated HBCs in placentas from pregnancies complicated by maternal infection and in vitro studies investigating HBC responses to pathogens or Pathogen-Associated Molecular Patterns (PAMPs). HBCs can be infected by a variety of pathogens, and HBC hyperplasia was a common observation. HBCs respond to pathogen infection and PAMPs by altering their transcriptional, translational and secretion profiles. Co-culture investigations demonstrate that they can replicate

Journal article

Oguti B, Ali A, Andrews N, Barug D, Duc AD, Halperin SA, Ha TTH, Holder B, Kampmann B, Kazi AM, Langley JM, Leuridan E, Madavan N, Maertens K, Maldonado H, Miller E, Munoz-Rivas FM, Omer SB, Pollard AJ, Rice TF, Rots N, Sundaram ME, Wanlapakorn N, Voysey Met al., 2022, The half-life of maternal transplacental antibodies against diphtheria, tetanus, and pertussis in infants: an individual participant data meta-analysis, VACCINE, Vol: 40, Pages: 450-458, ISSN: 0264-410X

Journal article

Skirrow H, Barnett S, Bell S, Riaposova L, Mounier-Jack S, Kampmann B, Holder Eet al., 2022, Women’s views on accepting COVID-19 vaccination during and after pregnancy, and for their babies: A multi-methods study in the UK., BMC Pregnancy and Childbirth, Vol: 22, Pages: 1-15, ISSN: 1471-2393

Background: COVID-19 vaccines are advised for pregnant women in the United Kingdom (UK) however COVID-19 vaccine uptake among pregnant women is inadequate. Methods: An online survey and semi-structured interviews were used to investigate pregnant women’s views on COVID-19 vaccine acceptability for themselves when pregnant, not pregnant and for their babies. 1,181 women, aged over 16 years, who had been pregnant since 23rd March 2020, were surveyed between 3rd August–11th October 2020. Ten women were interviewed. Results: The majority of women surveyed (81.2%) reported that they would ‘definitely’ or were ‘leaning towards’ accepting a COVID-19 vaccine when not pregnant. COVID-19 vaccine acceptance was significantly lower during pregnancy (62.1%, p<0.005) and for their babies (69.9%, p<0.005). Ethnic minority women were twice as likely to reject a COVID-19 vaccine for themselves when not pregnant, pregnant and for their babies compared to women from White ethnic groups (p<0.005). Women from lower-income households, aged under 25-years, and from some geographic regions were more likely to reject a COVID-19 vaccine when not pregnant, pregnant and for their babies. Multivariate analysis revealed that income and ethnicity were the main drivers of the observed age and regional differences. Women unvaccinated against pertussis in pregnancy were over four times more likely to reject COVID-19 vaccines when not pregnant, pregnant and for their babies. Thematic analysis of the survey freetext responses and interviews found safety concerns about COVID-19 vaccines were common though wider mistrust in vaccines was also expressed. Trust in vaccines and the health system were also reasons women gave for accepting COVID-19 vaccines.Conclusion: Safety information on COVID-19 vaccines must be clearly communicated to pregnant women to provide reassurance and facilitate informed pregnancy vaccine decisions. Targeted interventions to promote

Journal article

Rice T, Holder B, 2022, Determination of Maternal and Infant Immune Responses to Pertussis Vaccination in Pregnancy., Pages: 325-340

The Bordetella pertussis bacterium is the causative agent of whooping cough (pertussis disease). Following recent outbreaks of pertussis, disproportionately affecting young infants, several countries have introduced maternal pertussis vaccination strategies, aimed at boosting transplacental transfer of protective antibodies during pregnancy. Given historical associations between high maternal antibody and blunted infant responses to vaccination, subsequent research studies have investigated the impact of maternal pertussis vaccine on infant humoral responses. However, far less is known about the potential impact of the vaccine on innate immunity. Here, we describe methods to detect in vitro cellular responses to B. pertussis in mothers and their infants using a B. pertussis stimulation assay and multiplex cytokine assays to address this research question.

Book chapter

Holder B, Aplin JD, Gomez-Lopez N, Heazell AEP, James JL, Jones CJP, Jones H, Lewis RM, Mor G, Roberts CT, Robertson SA, Zenclussen ACet al., 2021, 'Fetal side' of the placenta: anatomical mis-annotation of carbon particle 'transfer' across the human placenta, NATURE COMMUNICATIONS, Vol: 12

Journal article

Abu-Raya B, Maertens K, Munoz FM, Zimmermann P, Curtis N, Halperin SA, Rots N, Barug D, Holder B, Rice TF, Kampmann B, Leuridan E, Sadarangani Met al., 2021, Factors affecting antibody responses to immunizations in infants born to women immunized against pertussis in pregnancy and unimmunized women: Individual-Participant Data Meta-analysis, Vaccine, Vol: 39, Pages: 6545-6552, ISSN: 0264-410X

BACKGROUND: Exploring factors that affect immune responses to immunizations in infants born to women immunized with tetanus-diphtheria-acellular-pertussis (Tdap) in pregnancy compared with unimmunized women is important in designing immunization programs. METHODS: Individual-participant data meta-analysis of 8 studies reporting post-immunization immunoglobulin G (IgG) levels to vaccine antigens in infants born to either women immunized with Tdap in pregnancy or unimmunized women, using mixed-effects models. RESULTS: In infants of Tdap-immunized women, two-fold higher levels of anti-pertussis toxin (PT) and anti-diphtheria-toxoid (DT) IgG pre-primary immunization were associated with 9% and 10% lower post-primary immunization levels, (geometric mean ratio [GMR], PT: 0.91; 95% CI, 0.88-0.95,n = 494, DT: 0.9; 0.87-0.93,n = 519). Timing of immunization in pregnancy did not affect post-primary immunization anti-Bordetella pertussis, anti-tetanus-toxoid (TT) and anti-DT IgG levels. Spacing of infant immunization did not affect post-primary immunization anti-B. pertussis and anti-DT levels. In infants of Tdap-immunized women, two-fold higher levels of anti-PT and anti-filamentous haemagglutinin (FHA) IgG pre-primary immunization were associated with lower post-booster immunization levels, (GMR, PT: 0.91; 0.85-0.97,n = 224, FHA: 0.92; 0.85-0.99,n = 232). Timing of immunization in pregnancy did not affect post-booster immunization anti-Bordetella pertussis, anti-tetanus-toxoid (TT) and anti-DT IgG levels. Spacing of infant immunization did not affect post-booster immunization anti-PT, anti-pertactin (PRN), anti-TT and anti-DT IgG levels. In infants of unimmunized women, two-fold higher IgG levels of some vaccine antigens pre-primary immunization were associated with 8-17% lower post-primary immunization levels (GMR, PT 0.92, 95% CI:0.88-0.97, n = 373; FHA:0.88, 95% CI:0.85-0.92,n = 378; PRN:0.84, 95% CI:0.81-0.88, n

Journal article

Rice TF, Diavatopoulos DA, Guo Y, Donaldson B, Bouqueau M, Bosanquet A, Barnett S, Holder B, Kampmann Bet al., 2021, Modification of innate immune responses to Bordetella pertussis in babies from pertussis vaccinated pregnancies, EBIOMEDICINE, Vol: 72, ISSN: 2352-3964

Journal article

Abu-Raya B, Maertens K, Munoz FM, Zimmermann P, Curtis N, Halperin SA, Rots N, Barug D, Holder B, Kampmann B, Leuridan E, Sadarangani Met al., 2021, The effect of tetanus-diphtheria-acellular-pertussis immunization during pregnancy on infant antibody responses: individual-participant data meta-analysis, Frontiers in Immunology, Vol: 12, Pages: 1-16

Background: Immunization with tetanus-diphtheria-acellular pertussis (Tdap) vaccine in pregnancy is increasingly recommended. We determined the effect of Tdap immunization in pregnancy on infants’ vaccine responses.Methods: Individual-participant data meta-analysis of ten studies (n=1884) investigating infants’ antibody response to routine immunizations following Tdap immunization in pregnancy was performed. Geometric mean ratios (GMRs) of antigen-specific immunoglobulin G (IgG) levels were calculated using mixed-effects models. Seroprotection rates were compared using chi-squared tests.Results: Infants of Tdap-immunized women had significantly lower IgG against pertussis toxin (GMR 0.65; 95%CI 0.57-0.74), filamentous haemagglutinin (FHA) (0.68; 0.53-0.87), pertactin (0.65; 0.58-0.72) and fimbria 2/3 (FIM2/3) (0.41; 0.32-0.52) after primary immunization, compared with infants of unimmunized women. These lower levels persisted after booster immunization for FHA (0.72; 0.61-0.84) and FIM2/3 (0.53; 0.29-0.96). After primary immunization, infants of Tdap-immunized women had lower seroprotection rates against diphtheria (90% [843/973] vs 98% [566/579]; p<0.001) and invasive pneumococcal disease (IPD) caused by 5 Streptococcus pneumoniae (SPN) serotypes (SPN5, SPN6B, SPN9V, SPN19A, SPN23F), and higher seroprotection rates against Haemophilus influenzae type b (short-term and long-term seroprotection rates, 86%[471/547] vs 76%[188/247] and 62%[337/547] vs 49%(121/247), respectively, all p=0.001). After booster immunization, seroprotection rates against diphtheria and tetanus were 99% (286/288) and (618/619) in infants of Tdap-immunized women, respectively.Conclusions: Infants of Tdap-immunized women in pregnancy had lower IgG levels against pertussis, diphtheria and some SPN serotypes after their immunization compared with infants of unimmunized women. Enhanced surveillance of pertussis, diphtheria and IPD in infants is needed to determine the clinical signi

Journal article

Skirrow H, Barnett S, Bell S, Riaposova L, Mounier-Jack S, Kampmann B, Holder Bet al., 2021, Women’s views on accepting COVID-19 vaccination during and after pregnancy, and for their babies: A multi-methods study in the UK, Publisher: Cold Spring Harbor Laboratory

Background COVID-19 vaccines are the cornerstone of the pandemic response and now advised for pregnant women in the United Kingdom(UK) however COVID-19 vaccine acceptance among pregnant women is unknown.Methods An online survey and semi-structured interviews were used to investigate pregnant women’s views on COVID-19 vaccine acceptability for themselves when pregnant, not pregnant and for their babies. 1,181 women, aged over 16 years, who had been pregnant since 23rd March 2020, were surveyed between 3rd August–11th October 2020. Ten women were interviewed.Results The majority of women surveyed (81.2%) reported that they would ‘definitely’ or were ‘leaning towards’ accepting a COVID-19 vaccine when not pregnant. COVID-19 vaccine acceptance was significantly lower during pregnancy (62.1%, p<0.005) and for their babies (69.9%, p<0.005). Ethnic minority women were twice as likely to reject a COVID-19 vaccine for themselves when not pregnant, pregnant and for their babies compared to women from White ethnic groups (p<0.005). Women from lower-income households, aged under 25-years, and from some geographic regions were more likely to reject a COVID-19 vaccine when not pregnant, pregnant and for their babies. Multivariate analysis revealed that income and ethnicity were the main drivers of the observed age and regional differences. Women unvaccinated against pertussis in pregnancy were over four times more likely to reject COVID-19 vaccines when not pregnant, pregnant and for their babies. Thematic analysis of the survey freetext responses and interviews found safety concerns about COVID-19 vaccines were common though wider mistrust in vaccines was also expressed. Trust in vaccines and the health system were also reasons women gave for accepting COVID-19 vaccines.Conclusion Safety information on COVID-19 vaccines must be clearly communicated to pregnant women to provide reassurance and facilitate informed pregnancy vaccine deci

Working paper

Skirrow H, Holder B, Meinel A, Narh E, Donaldson B, Bosanquet A, Barnett S, Kampmann Bet al., 2021, Evaluation of a midwife-led, hospital based vaccination service for pregnant women, Human Vaccines and Immunotherapeutics, Vol: 17, Pages: 237-246, ISSN: 1554-8600

BACKGROUND: Vaccines against whooping cough (pertussis) and seasonal-influenza are recommended for pregnant women in England. Uptake however varies regionally and by ethnicity. Pregnant women are traditionally vaccinated in primary care, though some hospitals now offer vaccines through antenatal clinics. This mixed-methods evaluation describes the demographic characteristics of women seen in a hospital midwife-led antenatal vaccine clinic and explores vaccine decision making. METHODS: Descriptive statistics of women seen in a London hospital's midwife-led vaccine clinic were generated from electronic routine maternity records, including data on ethnicity, parity, age and deprivation indices. Reasons for vaccine decline given by women to midwives were categorized by themes. Qualitative interviews of women seen in the clinic were also undertaken. RESULTS: Between 1st April 2017 and 31st March 2018 the vaccine clinic saw 1501 pregnant women. Of these, 83% received pertussis vaccine and (during flu season) 51% received influenza vaccine, from the clinic. Fewer Black Afro-Caribbean women seen by the clinic were vaccinated, compared to other ethnicities with only 68% receiving pertussis and 34% flu vaccines respectively (p < .05). Among all women delivering at the hospital over the year, 42%, (1334/3147) were vaccinated by the clinic. Qualitative interviews found that reassurance from healthcare professionals, particularly midwives, was the most important factor influencing maternal vaccine decisions. CONCLUSIONS: Midwife-led hospital clinics can offer an effective alternative to primary care provision for vaccines in pregnancy. Consistent with previous work, vaccine uptake varied by ethnicity. Midwives play a key role in the provision of vaccine services and influence women's vaccine decisions.

Journal article

Clements T, Rice T, Vamvakas G, Barnett S, Barnes M, Donaldson B, Christine J, Kampmann B, Holder Eet al., 2020, Update on trans-placental transfer of IgG subclasses: impact of maternal and fetal factors, Frontiers in Immunology, Vol: 11, Pages: 1-17, ISSN: 1664-3224

Transplacental antibody transfer from mother to fetus provides protection from infection in the first weeks of life, and the four different subclasses of IgG (IgG1, IgG2, IgG3, and IgG4) have diverse roles in protection against infection. In this study, we evaluated concentrations and transplacental transfer ratios of the IgG subclasses in a healthy UK-based cohort of mother-cord pairs, and investigated associations with maternal, obstetric, and fetal factors. In agreement with previous studies, we found a strong association between maternal and cord IgG for all subclasses. We report a transfer efficiency hierarchy of IgG1>IgG3>IgG4=IgG2 in our study population, and our review of the literature demonstrates that there is no consensus in the hierarchy of subclass transfer, despite the commonly made statement that the order is IgG1>IgG4>IgG3>IgG2. We report additional data regarding negative associations between elevated maternal IgG concentrations and maternal/cord transfer ratios, finding an effect on IgG1, IgG2, and IgG3 subclasses. Levels of IgG subclasses were the same between venous and arterial blood samples from the umbilical cord, but there was a significantly higher level of total IgG in arterial blood. We found no correlation between placental FcRn protein levels and IgG transfer in our cohort, suggesting that IgG is the main determinant of observed differences in transplacental transfer ratios at term. Neonatal IgG1 and IgG4 levels were increased with later gestation at delivery, independent of any increase in transplacental transfer, indicating that the benefit of later gestation is through accumulation of these subclasses in the fetus. Neonatal IgG2 levels and transfer ratios were reduced in rhesus-negative pregnancies, suggesting that administered anti-D antibodies may compete for transplacental transfer of this subclass. Maternal influenza vaccination resulted in elevated maternal and neonatal levels of IgG4, whereas maternal Tdap vaccin

Journal article

Basu Roy R, Sambou B, Sissoko M, Holder B, Gomez MP, Egere U, Sillah AK, Koukounari A, Kampmann Bet al., 2020, Protection against mycobacterial infection: A case-control study of mycobacterial immune responses in pairs of Gambian children with discordant infection status despite matched TB exposure, EBioMedicine, Vol: 59, Pages: 1-10, ISSN: 2352-3964

BackgroundChildren are particularly susceptible to tuberculosis. However, most children exposed to Mycobacterium tuberculosis are able to control the pathogen without evidence of infection. Correlates of human protective immunity against tuberculosis infection are lacking, and their identification would aid vaccine design.MethodsWe recruited pairs of asymptomatic children with discordant tuberculin skin test status but the same sleeping proximity to the same adult with sputum smear-positive tuberculosis in a matched case-control study in The Gambia. Participants were classified as either Highly TB-Exposed Uninfected or Highly TB-Exposed Infected children. Serial luminescence measurements using an in vitro functional auto-luminescent Bacillus Calmette–Guérin (BCG) whole blood assay quantified the dynamics of host control of mycobacterial growth. Assay supernatants were analysed with a multiplex cytokine assay to measure associated inflammatory responses.Findings29 pairs of matched Highly TB-Exposed Uninfected and Highly TB-Exposed Infected children aged 5 to 15 years old were enroled. Samples from Highly TB-Exposed Uninfected children had higher levels of mycobacterial luminescence at 96 hours than Highly TB-Exposed Infected children. Highly TB-Exposed Uninfected children also produced less BCG-specific interferon-γ than Highly TB-Exposed Infected children at 24 hours and at 96 hours.InterpretationHighly TB-Exposed Uninfected children showed less control of mycobacterial growth compared to Highly TB-Exposed Infected children in a functional assay, whilst cytokine responses mirrored infection status.FundingClinical Research Training Fellowship funded under UK Medical Research Council/Department for International Development Concordat agreement and part of EDCTP2 programme supported by European Union (MR/K023446/1). Also MRC Program Grants (MR/K007602/1, MR/K011944/1, MC_UP_A900/1122).

Journal article

Rice T, Holder E, Kampmann B, 2020, Antibody glycosylation in pregnancy and in newborns: biological roles and implications, Current Opinion in Infectious Diseases, Vol: 33, Pages: 225-230, ISSN: 0951-7375

Purpose of review Glycosylation patterns have the potential to affect the function of antibody, antibody half-life and transplacental transfer from mother to foetus. Here, we review recent advances in our understanding of how glycosylation patterns of antibodies may be altered during pregnancy, vaccination and infection.Recent findings During pregnancy, there is preferential transplacental transfer of natural killer (NK) cell-activating antibodies that are galactosylated and sialylated, against both bacterial and viral antigens. Markers of NK cell function are also associated with a higher abundance of galactosylation and sialylation in respiratory syncytial virus-specific IgG, compared with total IgG, in infants up to 7 months of age which may suggest a role for NK-cell activating antibodies as important mediators of immunity during early infancy. Differential glycosylation patterns have been observed in some respiratory conditions, as increased nongalactosylated antibodies have been associated with the development of chronic inflammatory bronchopulmonary dysplasia (BPD) in preterm infants. Glycosylation patterns in children appear age-dependent, which could modulate the effector function of IgG. The clinical relevance of these findings needs to be established.Summary Glycosylation plays a key role in mediating antibody function. Glycosylation patterns associated with positive outcomes from infection in mothers and infants could inform the design of the next generation of vaccines for use in pregnancy and infancy.

Journal article

Rice T, Diavatopoulos D, Smits G, van Gageldonk P, Berbers G, van der Klis F, Vamvakas G, Donaldson B, Bouqueau M, Holder B, Kampmann Bet al., 2019, Antibody responses to Bordetella pertussis and other childhood vaccines in infants born to mothers who received pertussis vaccine in pregnancy- a prospective, observational cohort study from the UK, Clinical and Experimental Immunology, Vol: 197, Pages: 1-10, ISSN: 1365-2249

The maternal Tdap (tetanus, diphtheria and acellular pertussis) vaccination program in the UK has successfully reduced cases of pertussis in young infants. In addition to prevention of pertussis cases, it is also important to investigate persistence of maternal antibody during infancy and possible interference of maternal antibodies with infant responses to vaccines. We recruited mother‐infant pairs from vaccinated and unvaccinated pregnancies and measured concentrations of IgG against pertussis toxin (PTx), filamentous hemagglutinin (FHA), pertactin (Prn), diphtheria toxin (DTx), tetanus toxoid (TTx) Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae in mothers and infants at birth, and in infants at 7 weeks and at 5 months. 31 mother‐infant pairs were tested. Tdap‐vaccinated women had significantly higher antibody against Tdap antigens, compared to unvaccinated women (DTx p=0.01; PTx, FHA, Prn and TTx p<0.001). All antibodies were actively transferred to the infants (transfer ratio >1) with higher transfer of DTx (P=0.04) and TTx (P=0.02) antibody in Tdap‐vaccinated pregnancies compared to unvaccinated. Infants from Tdap‐vaccinated pregnancies had significantly elevated antibodies to all antigens at birth (p<0.001) and at 7 weeks (FHA, Prn, TTx p<0.001; DTx p=0.01; PTx p=0.004) compared to infants from unvaccinated pregnancies. Infants from Tdap‐vaccinated and unvaccinated pregnancies had comparable antibody concentrations following primary pertussis immunization (PTx p=0.77; FHA p=0.58; Prn p=0.60; DTx p=0.09; TTx p=0.88). These results support maternal immunisation as a method of protecting vulnerable infants during their first weeks of life.

Journal article

Szymula A, Palermo RD, Bayoumy A, Groves IJ, Abdullah MB, Holder B, White REet al., 2019, Correction: Epstein-Barr virus nuclear antigen EBNA-LP is essential for transforming naive B cells, and facilitates recruitment of transcription factors to the viral genome, PLoS Pathogens, Vol: 15, ISSN: 1553-7366

In the original submission, the negative control in ChIP experiments was misidentified as detecting the myoglobin promoter: it in fact detects the myogenin promoter. As a result, there are textual errors in the captions for Fig 8, “Binding of EBNA2 to viral and host loci is influenced by EBNA-LP,” and Fig 9, “EBNA-LP enhances binding of host transcription factors RBPJ and EBF1 to viral but not host promoters.” There is also an ambiguity in the second table in the S3 Table file that has been clarified.

Journal article

Zhong Z, Haltalli M, Holder B, Rice T, Donaldson B, O'Driscoll M, Le-Doare K, Kampmann B, Tregoning JSet al., 2019, The impact of timing of maternal influenza immunisation on infant antibody levels at birth., Clinical and Experimental Immunology, Vol: 195, Pages: 139-152, ISSN: 1365-2249

Pregnant women and infants are at an increased risk of severe disease after influenza infection. Maternal immunisation is a potent tool to protect both of these at-risk groups. Whilst the primary aim of maternal influenza vaccination is to protect the mother, a secondary benefit is the transfer of protective antibodies to the infant. A recent study using the tetanus, diphtheria and acellular pertussis (Tdap) vaccine indicated that children born to mothers immunised in the second trimester of pregnancy had the highest antibody titres compared to children immunised in the third trimester. The aim of the current study was to investigate how timing of maternal influenza immunisation impacts infant antibody levels at birth. Antibody titres were assessed in maternal and cord blood samples by both IgG-binding ELISA and haemagglutination inhibition assay (HAI). Antibody titres to the H1N1 component were significantly higher in infants born to mothers vaccinated in either the second or third trimesters than infants born to unvaccinated mothers. HAI levels in the infant were significantly lower when maternal immunisation was performed less than four weeks before birth. These studies confirm that immunisation during pregnancy increases the antibody titre in infants. Importantly antibody levels in cord blood were significantly higher when mother was vaccinated in either trimester two or three, though titres were significantly lower if the mother was immunised less than 4 weeks before birth. Based on this data, seasonal influenza vaccination should continue to be given in pregnancy as soon as it becomes available.

Journal article

Thery C, Witwer KW, Aikawa E, Jose Alcaraz M, Anderson JD, Andriantsitohaina R, Antoniou A, Arab T, Archer F, Atkin-Smith GK, Ayre DC, Bach J-M, Bachurski D, Baharvand H, Balaj L, Baldacchino S, Bauer NN, Baxter AA, Bebawy M, Beckham C, Zavec AB, Benmoussa A, Berardi AC, Bergese P, Bielska E, Blenkiron C, Bobis-Wozowicz S, Boilard E, Boireau W, Bongiovanni A, Borras FE, Bosch S, Boulanger CM, Breakefield X, Breglio AM, Brennan MA, Brigstock DR, Brisson A, Broekman MLD, Bromberg JF, Bryl-Gorecka P, Buch S, Buck AH, Burger D, Busatto S, Buschmann D, Bussolati B, Buzas E, Byrd JB, Camussi G, Carter DRF, Caruso S, Chamley LW, Chang Y-T, Chen C, Chen S, Cheng L, Chin AR, Clayton A, Clerici SP, Cocks A, Cocucci E, Coffey RJ, Cordeiro-da-Silva A, Couch Y, Coumans FAW, Coyle B, Crescitelli R, Criado MF, D'Souza-Schorey C, Das S, Chaudhuri AD, de Candia P, De Santana Junior EF, De Wever O, del Portillo HA, Demaret T, Deville S, Devitt A, Dhondt B, Di Vizio D, Dieterich LC, Dolo V, Dominguez Rubio AP, Dominici M, Dourado MR, Driedonks TAP, Duarte F, Duncan HM, Eichenberger RM, Ekstrom K, Andaloussi SEL, Elie-Caille C, Erdbrugger U, Falcon-Perez JM, Fatima F, Fish JE, Flores-Bellver M, Forsonits A, Frelet-Barrand A, Fricke F, Fuhrmann G, Gabrielsson S, Gamez-Valero A, Gardiner C, Gaertner K, Gaudin R, Gho YS, Giebel B, Gilbert C, Gimona M, Giusti I, Goberdhan DC, Goergens A, Gorski SM, Greening DW, Gross JC, Gualerzi A, Gupta GN, Gustafson D, Handberg A, Haraszti RA, Harrison P, Hegyesi H, Hendrix A, Hill AF, Hochberg FH, Hoffmann KF, Holder B, Holthofer H, Hosseinkhani B, Hu G, Huang Y, Huber V, Hunt S, Ibrahim AG-E, Ikezu T, Inal JM, Isin M, Ivanova A, Jackson HK, Jacobsen S, Jay SM, Jayachandran M, Jenster G, Jiang L, Johnson SM, Jones JC, Jong A, Jovanovic-Talisman T, Jung S, Kalluri R, Kano S-I, Kaur S, Kawamura Y, Keller ET, Khamari D, Khomyakova E, Khvorova A, Kierulf P, Kim KP, Kislinger T, Klingeborn M, Klinke DJ, Kornek M, Kosanovic MM, Kovacs AF, Kraemer-Albers E-Met al., 2018, Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines, Journal of Extracellular Vesicles, Vol: 7, ISSN: 2001-3078

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.

Journal article

Rice T, Donaldson B, Bouqueau M, Kampmann B, Holder Bet al., 2018, Macrophage- but not monocyte-derived extracellular vesicles induce placental pro-inflammatory responses, Placenta, Vol: 69, Pages: 92-95, ISSN: 0143-4004

The placenta sheds extracellular vesicles (EVs), including exosomes, into the maternal circulation. We recently demonstrated that this trafficking of EVs is bi‐directional; with uptake of macrophage exosomes by the placenta inducing cytokine release. The specificity of this response is currently unknown. THP-1 cells were cultured as monocytes or differentiated to macrophages, and EVs isolated by ultra-centrifugation. The effect of EVs on human placental explants was measured by cytokine ELISA/luminex. Macrophage, but not monocyte, EVs induce the release of pro-inflammatory cytokines by the placenta. Thus, placental responses to immune cell EVs, including exosomes, reflects the phenotype of the source cell.

Journal article

Le Doare K, Holder B, Bassett A, Pannaraj Pet al., 2018, Mother’s milk: A purposeful contribution to the development of the infant microbiota and immunity, Frontiers in Immunology, Vol: 9, ISSN: 1664-3224

Breast milk is the perfect nutrition for infants, a result of millions of years of evolution. In addition to providing a source of nutrition, breast milk contains a diverse array of microbiota and myriad biologically active components that are thought to guide the infant’s developing mucosal immune system. It is believed that bacteria from the mother’s intestine may translocate to breast milk and dynamically transfer to the infant. Such interplay between mother and her infant is a key to establishing a healthy infant intestinal microbiome. These intestinal bacteria protect against many respiratory and diarrheal illnesses, but are subject to environmental stresses such as antibiotic use. Orchestrating the development of the microbiota are the human milk oligosaccharides (HMOs), the synthesis of which are partially determined by the maternal genotype. HMOs are thought to play a role in preventing pathogenic bacterial adhesion though multiple mechanisms, while also providing nutrition for the microbiome. Extracellular vesicles (EVs), including exosomes, carry a diverse cargo, including mRNA, miRNA, and cytosolic and membrane-bound proteins, and are readily detectable in human breast milk. Strongly implicated in cell–cell signaling, EVs could therefore may play a further role in the development of the infant microbiome. This review considers the emerging role of breast milk microbiota, bioactive HMOs, and EVs in the establishment of the neonatal microbiome and the consequent potential for modulation of neonatal immune system development.

Journal article

Szymula A, Palermo RD, Bayoumy A, Groves IJ, Abdulla MB, Holder B, White REet al., 2018, Epstein-Barr virus nuclear antigen EBNA-LP is essential for transforming naive B cells, and facilitates recruitment of transcription factors to the viral genome, PLoS Pathogens, Vol: 14, Pages: 1-34, ISSN: 1553-7366

The Epstein-Barr virus (EBV) nuclear antigen leader protein (EBNA-LP) is the first viral latency-associated protein produced after EBV infection of resting B cells. Its role in B cell transformation is poorly defined, but it has been reported to enhance gene activation by the EBV protein EBNA2 in vitro. We generated EBNA-LP knockout (LPKO) EBVs containing a STOP codon within each repeat unit of internal repeat 1 (IR1). EBNA-LP-mutant EBVs established lymphoblastoid cell lines (LCLs) from adult B cells at reduced efficiency, but not from umbilical cord B cells, which died approximately two weeks after infection. Adult B cells only established EBNA-LP-null LCLs with a memory (CD27+) phenotype. Quantitative PCR analysis of virus gene expression after infection identified both an altered ratio of the EBNA genes, and a dramatic reduction in transcript levels of both EBNA2-regulated virus genes (LMP1 and LMP2) and the EBNA2-independent EBER genes in the first 2 weeks. By 30 days post infection, LPKO transcription was the same as wild-type EBV. In contrast, EBNA2-regulated cellular genes were induced efficiently by LPKO viruses. Chromatin immunoprecipitation revealed that EBNA2 and the host transcription factors EBF1 and RBPJ were delayed in their recruitment to all viral latency promoters tested, whereas these same factors were recruited efficiently to several host genes, which exhibited increased EBNA2 recruitment. We conclude that EBNA-LP does not simply co-operate with EBNA2 in activating gene transcription, but rather facilitates the recruitment of several transcription factors to the viral genome, to enable transcription of virus latency genes. Additionally, our findings suggest that EBNA-LP is essential for the survival of EBV-infected naïve B cells.

Journal article

Wilcox CR, Holder E, Jones CE, 2017, Factors affecting the FcRn-mediated transplacental transfer of antibodies and implications for vaccination in pregnancy, Frontiers in Immunology, Vol: 8, ISSN: 1664-3224

At birth, neonates are particularly vulnerable to infection and transplacental transfer of immunoglobulin G (IgG) from mother to fetus provides crucial protection in the first weeks of life. Transcytosis of IgG occurs via binding with the neonatal Fc receptor (FcRn) in the placental synctiotrophoblast. As maternal vaccination becomes an increasingly important strategy for the protection of young infants, improving our understanding of transplacental transfer and the factors that may affect this will become increasingly important, especially in low-income countries where the burden of morbidity and mortality is highest. This review highlights factors of relevance to maternal vaccination that may modulate placental transfer—IgG subclass, glycosylation of antibody, total maternal IgG concentration, maternal disease, infant gestational age, and birthweight—and outlines the conflicting evidence and questions that remain regarding the complexities of these relationships. Furthermore, the intricacies of the Ab–FcRn interaction remain poorly understood and models that may help address future research questions are described.

Journal article

Rice T, Kampmann B, Holder B, 2017, One size fits all? Antibody avidity measurement against multiple antigens in maternal vaccination studies, Virulence, Vol: 8, Pages: 1066-1068, ISSN: 2150-5608

Journal article

Grant CR, Holder BS, Liberal R, Heneghan MA, Ma Y, Mieli-Vergani G, Vergani D, Longhi MSet al., 2017, Immunosuppressive drugs affect interferon (IFN)-γ and programmed cell death 1 (PD-1) kinetics in patients with newly diagnosed autoimmune hepatitis., Clinical and Experimental Immunology, Vol: 189, Pages: 71-82, ISSN: 1365-2249

Autoimmune hepatitis (AIH) is characterized by overwhelming effector immune responses associated with defective regulatory T cells (Tregs ). Several lines of evidence indicate CD4 as the main effectors involved in autoimmune liver damage. Herein we investigate the in-vitro effects of prednisolone, 6-mercaptopurine, cyclosporin, tacrolimus, mycophenolic acid (MPA) and rapamycin, immunosuppressive drugs (ISDs) used in AIH treatment, on the expression of proinflammatory cytokines, co-inhibitory molecules and ability to proliferate of CD4(+) CD25(-) cells, isolated from the peripheral blood of treatment-naive patients with AIH. We note that in healthy subjects (HS) following polyclonal stimulation and in the absence of ISDs, the expression of interferon (IFN)-γ, interleukin (IL)-17 and tumour necrosis factor (TNF)-α by CD4 effectors peaks at 48 h and decreases at 96 h to reach baseline levels. In contrast, in AIH the expression of all these proinflammatory cytokines continue rising between 48 and 96 h. Levels of programmed cell death-1 (PD-1), T cell immunoglobulin and mucin domain-containing molecule-3 (TIM-3) and cytotoxic T lymphocyte antigen-4 (CTLA-4) increase over 96-h culture both in HS and AIH, although with faster kinetics in the latter. Exposure to ISDs contains IFN-γ and PD-1 expression in AIH, where control over CD4(+) CD25(-) cell proliferation is also noted upon exposure to MPA. Treatment with tacrolimus and cyclosporin render CD4(+) CD25(-) cells more susceptible to Treg control. Collectively, our data indicate that in treatment-naive patients with AIH, all ISDs restrain T helper type 1 (Th1) cells and modulate PD-1 expression. Furthermore, they suggest that tacrolimus and cyclosporin may ameliorate effector cell responsiveness to Tregs .

Journal article

Holder BS, Jones T, Sancho Shimizu V, Rice TF, Donaldson B, Bouqueau M, Forbes K, Kampmann Bet al., 2016, Macrophage exosomes induce placental inflammatory cytokines: a novel mode of maternal-placental messaging, Traffic, Vol: 17, Pages: 168-178, ISSN: 1600-0854

During pregnancy, the placenta forms the interface between mother and fetus. Highly controlled regulation of trans-placental trafficking is therefore essential for the healthy development of the growing fetus. Extracellular vesicle-mediated transfer of protein and nucleic acids from the human placenta into the maternal circulation is well documented; the possibility that this trafficking is bi-directional has not yet been explored but could affect placental function and impact on the fetus. We hypothesized that the ability of the placenta to respond to maternal inflammatory signals is mediated by the interaction of maternal immune cell exosomes with placental trophoblast. Utilizing the BeWo cell line and whole placental explants, we demonstrated that the human placenta internalizes macrophage-derived exosomes in a time- and dose-dependent manner. This uptake was via clathrin-dependent endocytosis. Furthermore, macrophage exosomes induced release of proinflammatory cytokines by the placenta. Taken together, our data demonstrates that exosomes are actively transported into the human placenta and that exosomes from activated immune cells modulate placental cytokine production. This represents a novel mechanism by which immune cells can signal to the placental unit, potentially facilitating responses to maternal inflammation and infection, and thereby preventing harm to the fetus.

Journal article

Liberal R, Grant CR, Holder BS, Ma Y, Heneghan MA, Mieli-Vergani G, Vergani D, Longhi MSet al., 2015, In autoimmune liver disease defective regulatory T cell responsiveness to IL-2 results in low IL-10 production and impaired suppression, 66th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD), Publisher: WILEY-BLACKWELL, Pages: 364A-364A, ISSN: 0270-9139

Conference paper

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