Regulatory T cells: new keys for further unlocking the enigma of fetal tolerance and pregnancy complications.

The immunological alterations required for successful pregnancy in eutherian placental mammals have remained a scientific enigma since the discovery of MHC haplotype diversity and unique immune signatures among individuals. Within the past 10 years, accumulating data suggest that immune-suppressive regulatory T cells (Tregs) confer essential protective benefits in sustaining tolerance to the semiallogeneic fetus during pregnancy, along with their more established roles in maintaining tolerance to self and "extended self" commensal Ags that averts autoimmunity. Reciprocally, many human pregnancy complications stemming from inadequacies in fetal tolerance have been associated with defects in maternal Tregs. Thus, further elucidating the immunological shifts during pregnancy not only have direct translational implications for improving perinatal health, they have enormous potential for unveiling new clues about how Tregs work in other biological contexts. In this article, epidemiological data in human pregnancy and complementary animal studies implicating a pivotal protective role for maternal Tregs are summarized.

Vaccine preparation time, errors, satisfaction, and preference of prefilled syringes versus RSV vaccines requiring reconstitution: randomized, time and motion study.

AIM: The current study compared preparation time, errors, satisfaction, and preference for a prefilled syringe (PFS) versus two RSV vaccines requiring reconstitution (VRR1 and VRR2) in a randomized, single-blinded time and motion study. METHODS: Pharmacists, nurses, and pharmacy technicians were randomized to a preparation sequence of the three vaccines. Participants read instructions, then consecutively prepared the three vaccines with a 3-5-min washout period in between. Preparations were video recorded and reviewed by a trained pharmacist for preparation time and errors using predefined, vaccine-specific checklists. Participant demographics, satisfaction with vaccine preparation, and vaccine preference were recorded. Within-subjects analysis of variance was used to compare preparation time. Mixed-effects Poisson and ordered logistic regression models were used to compare the number of preparation errors and satisfaction scores, respectively. RESULTS: Sixty-three pharmacists (60%), nurses (35%), and pharmacy technicians (5%) participated at four sites in the United States. The least squares mean preparation time per dose for PFS was 141.8 s (95% CI = 156.8-126.7; p <.0001) faster than for VRR1, 103.6 s (95% CI = 118.7-88.5; p <.0001) faster than for VRR2, and 122.7 s (95% CI = 134.2-111.2; p <.0001) faster than the pooled VRRs. Overall satisfaction (combined "Very" and "Extremely") was 87.3% for PFS, 28.6% for VRR1, and 47.6% for VRR2. Most participants (81.0%) preferred the PFS vaccine. LIMITATIONS: The study is limited by the inability to completely blind observers. To minimize the effects of order, we utilized a 3-sequence block design; however, the order in which the vaccines were prepared may have affected outcomes. Participants were assessed once, whereas if repeated preparations were performed there may have been trained efficiencies gained for each vaccine. CONCLUSION: PFS vaccines can greatly simplify the vaccine preparation process, allowing administrators to prepare almost four times more doses per hour than with vial and syringe systems.

Influenza or Meningococcal Immunization During Pregnancy and Mortality in Women and Infants: A Pooled Analysis of Randomized Controlled Trials.

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

Efficacy, duration of protection, birth outcomes, and infant growth associated with influenza vaccination in pregnancy: a pooled analysis of three randomised controlled trials.

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

Maternal Influenza Immunization and Prevention of Severe Clinical Pneumonia in Young Infants: Analysis of Randomized Controlled Trials Conducted in Nepal, Mali and South Africa.

BACKGROUND: To evaluate the effect of antenatal influenza vaccination on all-cause severe infant pneumonia, we performed pooled analysis of 3 randomized controlled trials conducted in Nepal, Mali and South Africa. METHODS: The trials were coordinated from the planning phase. The follow-up period was 0-6 months postpartum in Nepal and Mali and 0-24 weeks in South Africa. Pregnant women with gestational age 17-34 weeks in Nepal, ≥28 weeks in Mali and 20-36 weeks in South Africa were enrolled. Trivalent inactivated influenza vaccine (IIV) was compared with either saline placebo (Nepal and South Africa) or quadrivalent meningococcal conjugate vaccine (Mali). In South Africa, cases were hospitalized and were therefore considered to have severe pneumonia. In Nepal and Mali, severe infant pneumonia diagnosis was based on the WHO Integrated Management of Childhood Illness definition. RESULTS: A total of 10,002 mothers and 9801 live-born eligible infants were included in the present analysis. There was a 31% lower incidence rate of severe pneumonia in the IIV group compared with the control group in Nepal [incidence rate ratio (IRR): 0.69; 95% CI: 0.50-0.94; ]. In South Africa, there was a 43% lower incidence rate of severe pneumonia in the IIV group versus the control group (IRR: 0.57; 95% CI: 0.33-1.0). There was no difference in incidence rates between the IIV group and the control group in Mali. Overall, incidence rate of severe pneumonia was 20% lower in the IIV group compared with the control group (IRR: 0.80; 95% CI: 0.66-0.99; P = 0.04). Protection was highest in the high influenza circulation period (IRR: 0.44; 95% CI: 0.23-0.84). CONCLUSIONS: Maternal influenza immunization may reduce severe pneumonia episodes among infants-particularly those too young to be completely vaccinated against Streptococcus pneumoniae and influenza.

Perinatal Listeria monocytogenes susceptibility despite preconceptual priming and maintenance of pathogen-specific CD8(+) T cells during pregnancy.

Listeria monocytogenes (Lm) is an intracellular bacterium with unique predisposition for systemic maternal infection during pregnancy and morbid consequences for the developing fetus. Given the high mortality associated with prenatal Lm infection, strategies for augmenting protective immunity during the exceedingly vulnerable period of pregnancy are urgently needed. Herein, protection conferred by attenuated Lm administered before pregnancy against subsequent virulent Lm prenatal infection was evaluated. We show that protection against secondary Lm infection in non-pregnant mice is sharply moderated during allogeneic pregnancy because significantly more bacteria are recovered from maternal tissues, despite the numerical and functional preservation of pathogen-specific CD8(+) T cells. More importantly, preconceptual priming does not protect against in utero invasion or fetal wastage because mice inoculated with attenuated Lm prior to pregnancy and naive pregnant controls each showed near complete fetal resorption and pathogen recovery from individual concepti after Lm infection during pregnancy. Remarkably, the lack of protection against prenatal Lm infection with preconceptual priming in allogeneic pregnancy is restored during syngeneic pregnancy. Thus, maternal-fetal antigen discordance dictates the ineffectiveness of preconceptual vaccination against fetal complications after prenatal Lm infection, despite the numerical and functional preservation of pathogen-specific CD8(+) T cells.

Pregnancy-induced maternal regulatory T cells, bona fide memory or maintenance by antigenic reminder from fetal cell microchimerism?

Long-term maintenance of immune components with defined specificity, without antigen is the hallmark feature of immunological memory. However, there are fundamental differences in how memory CD8(+) compared with CD4(+) T cells are maintained. After complete antigen elimination, CD8(+) T cells can persist as a self-renewing numerically stable cell population, and therefore satisfy the most stringent definition of "memory." Comparatively, CD4(+) T cell maintenance is considerably less stable, often requiring low-level antigen persistence or antigenic reminders. Recent studies show these basic memory features, classically ascribed to effector CD8(+) and CD4(+) T cells, extend to immune suppressive Foxp3(+) regulatory CD4(+) T cells (Tregs). In particular, gestational expansion and postpartum retention of maternal Tregs with fetal specificity may explain the protective benefits of primary pregnancy on complications in subsequent pregnancy. Herein, the possibility of ongoing antigenic reminders from fetal cell microchimerism in postpartum maintenance of maternal Tregs with fetal specificity is considered.