Half-life Estimation of Pertussis-Specific Maternal Antibodies in (Pre)Term Infants After In-Pregnancy Tetanus, Diphtheria, Acellular Pertussis Vaccination.

BACKGROUND: To reduce the risk of pertussis-related morbidity and mortality in early life, an increasing number of countries recommend maternal pertussis vaccination. However, there is limited knowledge about half-lives of vaccine-induced pertussis-specific maternal antibodies, especially in preterm infants, and factors potentially influencing them. METHODS: We compared 2 different approaches to provide estimates of the half-lives of pertussis-specific maternal antibodies in infants and explored potential effects on the half-life in 2 studies. In the first approach, we estimated the half-lives per child and used these estimates as responses in linear models. In the second approach, we used linear mixed effect models on a log2 transformed scale of the longitudinal data to use the inverse of the time parameter as an estimate for the half-lives. RESULTS: Both approaches provided similar results. The identified covariates partly explain differences in half-life estimates. The strongest evidence we observed was a difference between term and preterm infants, with the preterm infants showing a longer half-life. Among others, a longer interval between vaccination and delivery increases the half-life. CONCLUSIONS: Several variables influence the decay speed of maternal antibodies. Both approaches have advantages and disadvantages, while the choice is secondary when assessing the half-life of pertussis-specific antibodies. CLINICAL TRIALS REGISTRATION: NCT02408926 and NCT02511327.

Pertussis Immunization During Pregnancy: Assessment of the Role of Maternal Antibodies on Immune Responses in Term and Preterm-Born Infants.

BACKGROUND: Limited data exist on the impact of maternal tetanus, diphtheria, acellular pertussis (Tdap) vaccination for preterm born infants. We report its effect at birth and on antibody-mediated immune responses to a DTaP-IPV-HB-PRP~T vaccine in preterm compared with term infants. METHODS: Women delivering at term or prematurely were either vaccinated with a Tdap vaccine (Boostrix; GSK) during pregnancy or not vaccinated in the last 5 years. Cord and maternal blood were collected at delivery. Infants were vaccinated with DTaP-IPV-HB-PRP~T vaccine (Hexyon; Sanofi Pasteur) and blood collected before and 1 month after primary (8-12-16 weeks) and before and 1 month after booster vaccination (13 or 15 months for preterm and term, respectively). Immunoglobulin G antibodies against all antigens included in DTaP-IPV-HB-PRP~T vaccine were measured (NCT02511327). RESULTS: Cord blood geometric mean concentrations (GMCs) in preterm infants from Tdap-vaccinated women were significantly higher than in term and preterm infants from unvaccinated women. A longer time interval between maternal vaccination and delivery resulted in higher cord blood GMCs in preterm infants. Equal GMCs in term and preterm infants from Tdap-vaccinated women were observed after primary vaccination. After boosting, significantly lower GMCs were seen for pertussis toxin, filamentous hemagglutinin, and tetanus toxoid in preterm compared with term infants from Tdap-vaccinated women, yet still comparable to GMCs in both term and preterm infants from unvaccinated women. CONCLUSIONS: Preterm infants profit from maternal Tdap vaccination. Prematurity did not influence primary immune responses in the presence of maternal antibodies but was associated with a lower booster immune response.

Impact of Maternal Pertussis Antibodies on the Infants' Cellular Immune Responses.

INTRODUCTION: Maternal antibody interference of the infant's humoral immune responses raises some concern to the strategy of maternal Tdap (tetanus, diphtheria, acellular pertussis [aP]) vaccination. This study assessed the impact of maternal Tdap antibodies on the infant's pertussis-specific T lymphocyte responses following infant vaccination with an aP containing vaccine, in a term and preterm born cohort. METHODS: Heparin samples (±0.5 mL) were conveniently drawn from infants of a Belgian prospective cohort study (N = 79, NCT02511327), including Tdap vaccinated (Boostrix®) and nonvaccinated women (no Tdap vaccine in the last 5 years) that delivered at term or prematurely. Sampling was performed before and 1 month after primary (8-12-16 weeks) and booster vaccination (13 or 15 months) with DTaP-IPV-HB-PRP~T vaccine (Hexyon®). Pertussis toxin (PT)-specific CD3+, CD3+ CD4+ and CD3+ CD8+ lymphoblasts and their cytokine secretions were measured using a flow cytometric assay on whole blood (FASCIA) and multiplex technology (Meso Scale Discovery), respectively. RESULTS: In total, 57% of all infants were considered PT-specific CD3+ CD4+ lymphoblasts responders after primary and booster vaccination, whereas 17% were CD3+ CD8+ lymphoblast responders. Interferon (IFN)-γ, interleukin (IL)-13, IL-17A, and IL-5 cytokine secretions after primary and booster vaccination were indicative of a mixed T helper (Th) 1/Th2/Th17 cell profile. Lymphoblast and cytokine levels were comparable between term and preterm infants. Nonresponders for IL-13 after booster vaccination had higher maternal PT immunoglobulin G (IgG) levels at birth when compared to responders. CONCLUSIONS: Term and preterm born infants are capable of inducing Th1, Th2, and Th17 responses after aP vaccination, yet maternal vaccination modulate these responses. Evaluation of this effect in larger trials is needed.

Breast Milk Antibody Levels in Tdap-Vaccinated Women After Preterm Delivery.

BACKGROUND: Enrichment of breast milk (BM) with immunoglobulin (Ig) A and IgG through maternal vaccination could help infants combat targeted pathogens. However, evidence on this effect after preterm delivery is lacking. In this study, we investigated the total and anti-pertussis toxin (anti-PT)-specific IgA and IgG production in BM after term and preterm delivery in the presence of maternal Tdap (tetanus, diphtheria, acellular pertussis) vaccination. METHODS: Serum and BM samples of lactating women who delivered at term or prematurely and did or did not receive Tdap vaccine (Boostrix, GSK Biologicals) during pregnancy were collected as part of a clinical study (N = 234). Anti-PT IgA/IgG (IBL assay; Meso Scale Discovery assay) and total IgA/IgG (Thermofisher, on BM samples only) immunosorbent assays were performed on all samples collected at 72 hours and 4, 8, and 12 weeks postpartum. RESULTS: BM after preterm delivery contained anti-PT IgA and IgG geometric mean concentrations (GMCs) comparable to those after term delivery (eg, colostrum anti-PT IgA, 5.39 IU/mL vs 6.69 IU/mL, respectively). Maternal Tdap vaccination induced significantly higher anti-PT IgG GMCs in colostrum of vaccinated compared with unvaccinated women who delivered at term (0.110 IU/mL vs 0.027 IU/mL, P = .009). Anti-PT antibodies persisted up to 12 weeks postpartum. CONCLUSIONS: This study provides evidence that maternal Tdap vaccination induces high Ig levels in BM after both term and preterm delivery and that these antibodies remain abundantly present throughout lactation, possibly offering additional mucosal protection during the most vulnerable period in early life. CLINICAL TRIAL REGISTRATION: NCT02511327.

Measuring association among censored antibody titer data.

Censoring due to a limit of detection or limit of quantification happens quite often in many medical studies. Conventional approaches to deal with censoring when analyzing these data include, for example, the substitution method and the complete case (CC) analysis. More recently, maximum likelihood estimation (MLE) has been increasingly used. While the CC analysis and the substitution method usually lead to biased estimates, the MLE approach appears to perform well in many situations. This article proposes an MLE approach to estimate the association between two measurements in the presence of censoring in one or both quantities. The central idea is to use a copula function to join the marginal distributions of the two measurements. In various simulation studies, we show that our approach outperforms existing conventional methods (CC and substitution analyses). In addition, rank-based measures of global association such as Kendall's tau or Spearman's rho can be studied, hence, attention is not only confined to Pearson's product-moment correlation coefficient capturing solely linear association. We have shown in our simulations that our approach is robust to misspecification of the copula function or marginal distributions given a small association. Furthermore, we propose a straightforward MLE method to fit a (multiple) linear regression model in the presence of censoring in a covariate or both the covariate and the response. Given the marginal distribution of the censored covariate, our method outperforms conventional approaches. We also compare and discuss the performance of our method with multiple imputation and missing indicator model approaches.

Quantity and Quality of Antibodies After Acellular Versus Whole-cell Pertussis Vaccines in Infants Born to Mothers Who Received Tetanus, Diphtheria, and Acellular Pertussis Vaccine During Pregnancy: A Randomized Trial.

BACKGROUND: The blunting effect of pertussis immunization during pregnancy on infant antibody responses induced by whole-cell pertussis (wP) vaccination is not well-defined. METHODS: This randomized controlled trial (NCT02408926) followed term infants born to mothers vaccinated with tetanus, diphtheria, and acellular pertussis (Tdap) vaccine during pregnancy in Thailand. Infants received either acellular pertussis (aP)- or wP-containing vaccine at 2, 4, 6, and 18 months of age. A comparison group comprised wP-vaccinated children born to mothers not vaccinated during pregnancy. Antibodies against pertussis toxin (PT), filamentous hemagglutinin (FHA), and pertactin (PRN) were evaluated using commercial enzyme-linked immunosorbent assays. Functionality of antibodies against Bordetella pertussis was measured using Bordetella pertussis growth inhibition assay. RESULTS: After maternal Tdap vaccination, 158 infants vaccinated with aP-containing vaccines possessed higher antibody levels (P < .001) against all tested B. pertussis antigens postpriming compared to 157 infants receiving wP-containing vaccines. At 1 month postbooster, only anti-FHA and anti-PRN antibodies were still significantly higher (P < .001) in the aP group. Significantly higher anti-PT and anti-FHA (P < .001), but not anti-PRN immunoglobulin G, were observed among 69 wP-vaccinated infants born to control mothers compared with wP-vaccinated infants of Tdap-vaccinated mothers after primary and booster vaccination. The antibody functionality was higher in all wP-vaccinated infants at all times. CONCLUSIONS: Maternal Tdap vaccination inhibited more pertussis-specific responses in wP-vaccinated infants compared to aP-vaccinated infants, and the control group of unvaccinated women had highest PT-specific responses, persisting until after the booster dose. Antibody functionality was better in the wP groups. CLINICAL TRIALS REGISTRATION: NCT02408926.Infant whole-cell pertussis (wP) vaccine responses are blunted after maternal Tdap vaccination. Pertussis antibody titers are higher in acellular pertussis (aP)- than wP-vaccinated infants of immunized mothers, yet quality of antibodies, measured as serum-mediated bacterial growth inhibition, is better after wP than aP vaccination.

Vaccination during pregnancy: current and possible future recommendations.

Immunizing pregnant women to protect the mother, fetus and infant from infection has increasingly been used over the last decade. Protection against infectious diseases in neonates is mainly provided by maternal antibodies transferred from mother to infant during pregnancy through transplacental transport or after delivery via breastfeeding. Both the transplacental- and breast milk-derived maternal antibodies function as the primary source of protection against infectious diseases in neonates during the first vulnerable weeks of life. During recent infectious disease outbreaks (influenza, pertussis, Zika…) and for other infectious diseases (CMV, GBS…), pregnant women are increasingly identified as an important target for vaccination. For some of these diseases, vaccines are already on the market, and recommended during pregnancy. For others, vaccines are currently under development; furthermore, some are even specifically designed to be administered during pregnancy.Conclusion: This review article provides an overview on the rationale and main mechanism of the maternal vaccination strategy and gives a summary about the current and possible future recommendations for maternal vaccination.What is Known:• Maternal vaccination has a far-reaching potential in the protection of both women and offspring.• Currently, tetanus, pertussis and influenza vaccination during pregnancy is recommended in some countries. Several new vaccines specifically designed for use in pregnancy are currently under development.What is New:• Review providing a timely overview of the rationale and main mechanisms of the maternal vaccination strategy• Up-to-date summary of the current and possible future recommendations for maternal vaccination.

Effect of Prepregnancy Pertussis Vaccination in Young Infants.

Background: Maternal antibodies to pertussis can hamper infant immune responses to pertussis vaccines. The effect a maternal tetanus, diphtheria, acellular pertussis (Tdap) vaccine booster between 2 consecutive pregnancies is investigated. Methods: A prospective study was conducted in Belgium during 2008-2014 on the kinetics of maternal pertussis antibodies in unvaccinated women and their infants (group A; 86 mother-infant pairs) and in siblings born after the women received Tdap vaccine (group B; 58 mother-infant pairs). Levels of antibody to pertussis toxin, antibody to filamentous hemagglutinin, and antibody to pertactin were measured in maternal blood before and after vaccination and at both deliveries, in cord blood from both siblings, and in infants before and after they received a priming series of acellular pertussis containing vaccines. Results: Levels of pertussis antibodies in all group B siblings at birth were significantly higher than those in their siblings at birth, even as the interval since maternal vaccination increased. Blunting of the infant pertussis vaccine response was detected in group B siblings. We estimated the maximum interval between repeat Tdap vaccine doses in adult women that would yield a beneficial effect for the consecutive infant. Conclusions: Prepregnancy Tdap vaccination significantly increases maternal antibody concentrations in consecutive infants. However, similar to the effect of Tdap vaccination during pregnancy, immune responses of later-born infants born to mothers who received a prepregnancy immunization, are blunted.

The Effect of Maternal Pertussis Immunization on Infant Vaccine Responses to a Booster Pertussis-Containing Vaccine in Vietnam.

BACKGROUND: Maternal vaccination with an acellular pertussis (aP)-containing vaccine is a recommended strategy in a growing number of industrialized countries, to protect young infants from disease. Little is known on the effect of this strategy in low- and middle-income countries. Following a previous report on the effect of adding a pertussis and diphtheria component to the tetanus vaccination program in pregnant women in Vietnam, we report on infant immune responses to a booster aP vaccine dose in this randomized controlled clinical trial. METHODS: Thirty infants of Tdap (tetanus, diphtheria, and acellular pertussis)-vaccinated pregnant women and 37 infants of women vaccinated with a tetanus-only vaccine received a fourth aP-containing vaccine dose in the second year of life. Blood was taken 1 month after the fourth infant dose. Immunoglobulin G (IgG) antibodies against pertussis toxin (PT), filamentous hemagglutinin (FHA), pertactin (Prn), tetanus toxoid (TT), and diphtheria toxoid (DT) were measured using commercially available enzyme-linked immunosorbent assays (ELISA). RESULTS: One month after the booster dose, significantly lower antibody titers were measured in the Tdap group for anti-TT IgG (P < .001) only. Anti-DT IgG, anti-PT IgG, anti-Prn IgG, and anti-FHA IgG antibody titers were comparable for both groups. A rise in antibody concentrations was elicited for all (except DT) antigens after boosting. CONCLUSIONS: The present results indicate that the blunting of infant pertussis responses induced by maternal immunization, measured after a primary series of aP vaccines, was resolved with the booster aP vaccine dose. These results add to the evidence for national and international decision makers on maternal immunization as a vaccination strategy for protection of young infants against infectious diseases.

Immunogenicity at delivery after Tdap vaccination in successive pregnancies.

Background: Tetanus, diphtheria, acellular pertussis (Tdap) vaccination is recommended to be administered in every pregnancy. Although the safety of this strategy has been confirmed, the immunogenicity of Tdap vaccination in two successive pregnancies has not yet been described. This study investigated Tdap-specific immunity levels and transplacental transfer in two successive pregnancies after repeated Tdap-vaccination. Methods: Women enrolled in prior studies on Tdap vaccination during pregnancy were invited to participate in a follow-up study if they became pregnant again. Women who received a Tdap vaccine in both pregnancies were considered for this analysis. Tdap-specific total IgG and IgG subclasses were measured with a multiplex immunoassay. Results: In total, 27 participants with a mean interval between deliveries of 2.4 years were included in the analysis. In maternal serum, Tdap-specific total IgG levels were comparable at both deliveries whereas in cord serum, all Tdap-specific total IgG antibody levels were reduced at the second compared to the first delivery. This was largely reflected in the IgG1 levels in maternal and cord serum. Transplacental transfer ratios of total IgG and IgG1 were also mostly reduced in the second compared to the first pregnancy. Conclusion: This study reports for the first time Tdap-specific total IgG and IgG subclass levels and transfer ratios after repeated Tdap vaccination in successive pregnancies. We found reduced transfer of most Tdap-specific IgG and IgG1 antibodies in the successive pregnancy. As pertussis-specific antibodies wane quickly, Tdap vaccination in each pregnancy remains beneficial. However, more research is needed to understand the impact of closely spaced booster doses during pregnancy on early infant protection against pertussis.

Timing of pertussis vaccination during pregnancy: Evidence and implementation - A systematic review.

BACKGROUND: Pertussis vaccination in pregnancy has been introduced in an increasing number of countries to better protect infants against the disease in their first weeks of life. The optimal timing of pertussis vaccination in pregnancy is however still under debate. METHODS: We systematically reviewed published literature on safety, immunogenicity and effectiveness of pertussis vaccination in pregnancy related to timing of vaccination. The search was conducted using PubMed, MEDLINE and Web of Science and yielded 1623 articles, thereof 777 duplicates. Screening resulted in the inclusion of 45 publications reporting on safety (n = 11), immunogenicity (n = 26) and/or effectiveness (n = 9). We also mapped pertussis recommendations in pregnancy by government institutions globally according to the recommended timing of vaccination. RESULTS: Overall, the selected publications did not indicate increased safety concerns associated with timing of pertussis vaccination in pregnancy. Immunogenicity studies often suggested optimal protection at birth after early third trimester vaccination. Few studies investigated qualitative antibody characteristics, and none investigated antibody titers in breastmilk or cellular-mediated immunity related to timing of vaccination. Effectiveness studies showed decreased vaccine effectiveness of late third trimester pertussis vaccination compared to vaccination earlier in pregnancy. Worldwide, a general recommendation for pertussis vaccination in pregnancy was found for 58 countries, with as many as 22 different recommended timings registered. CONCLUSION: The timing of pertussis vaccination in pregnancy seems to impact immunogenicity and vaccine effectiveness, with optimal immune responses at birth suggested following early third trimester vaccination and reduced vaccine effectiveness of late third trimester pertussis vaccination suggested compared to vaccination earlier in pregnancy. However, inconsistent and lacking data are reflected in the divergent national recommendations for pertussis vaccination in pregnancy worldwide. SUMMARY: Pertussis vaccination in pregnancy aims to protect infants in their first weeks of life. Our review suggests that immunogenicity and vaccine effectiveness are impacted by the timing of vaccination in pregnancy. National recommendations for pertussis vaccination in pregnancy vary widely worldwide.

Influence of the COVID-19 pandemic and social media on the behaviour of pregnant and lactating women towards vaccination: a scoping review.

BACKGROUND: Pregnant women, foetuses and infants are at risk of infectious disease-related complications. Maternal vaccination is a strategy developed to better protect pregnant women and their offspring against infectious disease-related morbidity and mortality. Vaccines against influenza, pertussis and recently also COVID-19 are widely recommended for pregnant women. Yet, there is still a significant amount of hesitation towards maternal vaccination policies. Furthermore, contradictory messages circulating social media impact vaccine confidence. OBJECTIVES: This scoping review aims to reveal how COVID-19 and COVID-19 vaccination impacted vaccine confidence in pregnant and lactating women. Additionally, this review studied the role social media plays in creating opinions towards vaccination in these target groups. ELIGIBILITY CRITERIA: Articles published between 23 November 2018 and 18 July 2022 that are linked to the objectives of this review were included. Reviews, articles not focusing on the target group, abstracts, articles describing outcomes of COVID-19 infection/COVID-19 vaccination were excluded. SOURCES OF EVIDENCE: The PubMed database was searched to select articles. Search terms used were linked to pregnancy, lactation, vaccination, vaccine hesitancy, COVID-19 and social media. CHARTING METHODS: Included articles were abstracted and synthesised by one reviewer. Verification was done by a second reviewer. Disagreements were addressed through discussion between reviewers and other researchers. RESULTS: Pregnant and lactating women are generally less likely to accept a COVID-19 vaccine compared with non-pregnant and non-nursing women. The main reason to refuse maternal vaccination is safety concerns. A positive link was detected between COVID-19 vaccine willingness and acceptance of other vaccines during pregnancy. The internet and social media are identified as important information sources for maternal vaccination. DISCUSSION AND CONCLUSION: Vaccine hesitancy in pregnant and lactating women remains an important issue, expressing the need for effective interventions to increase vaccine confidence and coverage. The role social media plays in vaccine uptake remains unclear.

Haemophilus influenzae carriage and antibiotic resistance profile in Belgian infants over a three-year period (2016-2018).

Background: Non-typeable Haemophilus influenzae has become increasingly important as a causative agent of invasive diseases following vaccination against H. influenzae type b. The emergence of antibiotic resistance underscores the necessity to investigate typeable non-b carriage and non-typeable H. influenzae (NTHi) in children. Methods: Nasopharyngeal swab samples were taken over a three-year period (2016-2018) from 336 children (6-30 months of age) attending daycare centers (DCCs) in Belgium, and from 218 children with acute otitis media (AOM). Biotype, serotype, and antibiotic resistance of H. influenzae strains were determined phenotypically. Mutations in the ftsI gene were explored in 129 strains that were resistant or had reduced susceptibility to beta-lactam antibiotics. Results were compared with data obtained during overlapping time periods from 94 children experiencing invasive disease. Results: Overall, NTHi was most frequently present in both carriage (DCC, AOM) and invasive group. This was followed by serotype "f" (2.2%) and "e" (1.4%) in carriage, and "b" (16.0%), "f" (11.7%), and "a" (4.3%) in invasive strains. Biotype II was most prevalent in all studied groups, followed by biotype III in carriage and I in invasive strains. Strains from both groups showed highest resistance to ampicillin (26.7% in carriage vs. 18.1% in invasive group). A higher frequency of ftsI mutations were found in the AOM group than the DCC group (21.6 vs. 14.9% - p = 0.056). Even more so, the proportion of biotype III strains that carried a ftsI mutation was higher in AOM compared to DCC (50.0 vs. 26.3% - p < 0.01) and invasive group. Conclusion: In both groups, NTHi was most frequently circulating, while specific encapsulated serotypes for carriage and invasive group were found. Biotypes I, II and III were more frequently present in the carriage and invasive group. The carriage group had a higher resistance-frequency to the analyzed antibiotics than the invasive group. Interestingly, a higher degree of ftsI mutations was found in children with AOM compared to DCC and invasive group. This data helps understanding the H. influenzae carriage in Belgian children, as such information is scarce.

The Effects of COVID-19 Vaccination on Lactating Women: A Systematic Review of the Literature.

Objectives: The availability of new vaccines against COVID-19 urges for guidance about vaccination during lactation. We aimed to review the literature to get an insight into the effects of COVID-19 vaccination on lactating women. Design: Systematic review. Data Sources: We searched Ovid Embase Classic+Embase, PubMed and BioMed Central for articles published between December 1st 2020 and December 31st 2021. Review Methods: The search strategy contained terms and combinations related to COVID-19 vaccination during lactation, including the MeSH terms "COVID-19", "COVID-19 Vaccines", "SARS-CoV-2", "Lactation", "Breast Feeding", "Pregnancy" and "Postpartum period". The database search was completed with a manual search of the reference lists of included articles. Data concerning country, study period, number of participants, type of applied vaccine, time points of sampling and outcome measures were collected from the selected manuscripts. The data are summarized and synthesized in a descriptive way. Results: 30 manuscripts were included in this review. Data on safety of COVID-19 vaccination during lactation indicate no severe vaccine-related local and systemic reactions, both after first and second dose, neither in the mother nor the nursing child. No significant amount of vaccine components seems to appear in breast milk. Milk supply data after vaccination are inconclusive as there are no quantitative data available. Some women however observe a temporary increase or reduction in milk supply, without long-term effects. All prospective cohort studies demonstrated the presence of SARS-CoV-2-specific antibodies in breast milk of nursing mothers vaccinated against SARS-CoV-2. Nearly all studies were conducted with mRNA vaccines. Conclusion: There is evidence that the administration of a COVID-19 vaccine is safe and poses no additional risk to the breastfeeding woman or the breastfed baby. After vaccination of the mother during the lactation period, antibodies appear in the milk, which could protect the infant against COVID-19. Professional associations and government health authorities should therefore recommend offering COVID-19 vaccines to breastfeeding women, as the potential benefits of maternal vaccination while breastfeeding outweigh the risks.

The Impact of Timing of Pertussis Vaccination During Pregnancy on Infant Antibody Levels at Birth: A Multi-Country Analysis.

Background: Pertussis vaccination during pregnancy is an effective strategy at reducing pertussis-related morbidity and mortality in infancy and is recommended across several countries. However, the optimal timepoint for vaccination in pregnancy to afford maximal protection to newborns is yet to be elucidated. This multi-country analysis aimed to model the impact of timing of vaccination during pregnancy on infant antibody titers at birth. Methods: A multi-country analysis on a cohort of mother-infant pairs (n=698) vaccinated between 19.6-37.1 weeks gestation was conducted. Data taken from four parent studies on pertussis vaccination during pregnancy were modelled using natural cubic splines and linear mixed models to study the association of both gestational age at vaccination and the interval between vaccination and delivery with pertussis-specific cord blood antibody levels after pertussis vaccination during pregnancy. Results: Term born infants on average achieve the highest antibody levels at birth if women are vaccinated before 31 weeks' gestation. When considering both term and preterm deliveries, an interval of at least 7.5 weeks between vaccination and delivery is required to achieve the highest cord blood antibody levels. The models show that vaccinating earlier than these timeframes will also provide the infant with equally high antibody levels at birth. Conclusions: Vaccinating in the second and early third trimester results in the highest antibody levels at birth. Vaccinating earlier within this window is needed to provide equal benefits to both term and preterm born infants.

Vaccination in Pregnancy against Pertussis: A Consensus Statement on Behalf of the Global Pertussis Initiative.

Infants are at high risk for severe morbidity and mortality from pertussis disease during early infancy. Vaccination against pertussis in pregnancy has emerged as the ideal strategy to protect infants during these early, vulnerable, first months of life. On 30 November and 1 December 2021, the Global Pertussis Initiative held a meeting that aimed to discuss and review the most up-to-date scientific literature supporting vaccination against pertussis in pregnancy and outstanding scientific questions. Herein, we review the current and historically published literature and summarize the findings as consensus statements on vaccination against pertussis in pregnancy on behalf of the Global Pertussis Initiative.

The half-life of maternal transplacental antibodies against diphtheria, tetanus, and pertussis in infants: an individual participant data meta-analysis.

AIM: There are few reliable estimates of the half-lives of maternal antibodies to the antigens found in the primary series vaccines. We aimed to calculate the half-lives of passively acquired diphtheria, tetanus and pertussis (DTP) antibodies in infants. We aimed to determine whether decay rates varied according to country, maternal age, gestational age, birthweight, World Bank income classifications, or vaccine received by the mother during pregnancy. METHODS: De-identified data from infants born to women taking part in 10 studies, in 9 countries (UK, Belgium, Thailand, Vietnam, Canada, Pakistan, USA, Guatemala and the Netherlands) were combined in an individual participant data meta-analysis. Blood samples were taken at two timepoints before any DTP-containing vaccines were received by the infant: at birth and at 2-months of age. Decay rates for each antigen were log2-transformed and a mixed effects model was applied. Half-lives were calculated by taking the reciprocal of the absolute value of the mean decay rates. RESULTS: Data from 1426 mother-infant pairs were included in the analysis. The half-lives of the 6 antigen-specific maternal antibodies of interest were similar, with point estimates ranging from 28.7 (95% CI: 24.4 - 35) days for tetanus toxoid antibodies to 35.1 (95% CI: 30.7 - 41.1) days for pertactin antibodies. The decay of maternal antibodies did not significantly differ by maternal age, gestational age, birthweight, maternal vaccination status or type of vaccine administered. CONCLUSION: Maternal antibodies decay at different rates for the different antigens; however, the magnitude of the difference is small. Decay rates are not modified by key demographic or vaccine characteristics.

Protection of the Newborn Through Vaccination in Pregnancy.

Newborns and infants are at risk for severe infections with some pathogens (eg, Bordetella pertussis, influenza, respiratory syncytial virus, group B Streptococcus) during early life. To decrease this window of high susceptibility to some infections during early life and protect young infants, vaccination in pregnancy against some vaccine-preventable diseases (eg, influenza, pertussis, tetanus) has been recommended in an increasing number of countries with notable success. In addition, recent advances have been made in developing vaccines for pregnant women with the aim of reducing the respiratory syncytial virus and group B Streptococcus burden in infancy. In this article, we review the vaccines currently recommended during pregnancy and their benefits to newborns and infants. We also discuss progress made in the development of other vaccines that are expected to be evaluated in pregnant women in the near future.

Factors affecting antibody responses to immunizations in infants born to women immunized against pertussis in pregnancy and unimmunized women: Individual-Participant Data Meta-analysis.

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 = 367; TT:0.88, 95% CI:0.83-0.93, n = 241; DT: 0.83, 95% CI:0.79-0.87,n = 278). Two-fold higher levels of anti-FHA IgG pre-primary immunization were associated with 8% lower post-booster immunization levels (GMR, 0.92; 95% CI: 0.86-0.99,n = 138). DISCUSSION: Increased IgG levels pre-primary immunization is associated with reduced post-primary and post-booster immunization levels for some antigens in infants of women immunized or unimmunized in pregnancy, but their clinical significance is uncertain.

The Effect of Tetanus-Diphtheria-Acellular-Pertussis Immunization During Pregnancy on Infant Antibody Responses: Individual-Participant Data Meta-Analysis.

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 significance of these findings. Systematic Review Registration: CRD42017079171.