Effects of Maternal HIV Infection on Early Kaposi Sarcoma-Associated Herpesvirus Seroconversion in a Kenyan Mother-Infant Cohort.

BACKGROUND: We identified whether maternal human immunodeficiency virus (HIV) infection during pregnancy affects transplacental transfer of Kaposi sarcoma-associated herpesvirus (KSHV)-specific antibodies and subsequent infant infection. METHODS: We followed pregnant Kenyan women through delivery and their infants until age 2 years. Children were classified as HIV-exposed uninfected (HEU) or HIV-unexposed uninfected (HUU) based on maternal HIV status. Maternal venous and cord blood at delivery and child venous blood every 6 months were tested for antibodies to 20 KSHV antigens by multiplex bead-based immunoassay. Multiple comparisons were adjusted using false discovery rate (FDR). RESULTS: Maternal HIV infection was significantly associated with decreased transplacental transfer of antibodies against all KSHV antigens and lower cord blood levels for 8 antigens at FDR P < .10. Neither birth to 6-month antibody level changes nor 6-month levels differed in HEU and HUU, except for ORF50. By age 24 months, 74% of children KSHV seroconverted but HEU and HUU did not differ in time to seroconversion nor 2-year seropositivity after adjustment for child malaria infection. CONCLUSIONS: Maternal HIV infection reduced a child's initial KSHV antibody levels but did not affect age of infection. Regardless of HIV exposure in utero, KSHV seroconversion in Kenyan children occurred early; associated factors must be identified.

Immune Response and Transplacental Antibody Transfer in Pregnant Women after COVID-19 Vaccination.

COVID-19 infection is associated with increased risk of pregnancy complications, making vaccination during pregnancy critical for mother-neonate dyads. Few data, often with an unrepresentative sample size, are available on SARS-CoV-2 vaccine-induced humoral and cell-mediated response. Here, we evaluated anti-S antibody and interferon-gamma (IFN-γ) production elicited by SARS-CoV-2 immunization in maternal and neonatal plasma. Pregnant women (n = 230) were prospectively enrolled and classified as unvaccinated (n = 103) and vaccinated (n = 127); after serological screening for previous infections, assays were performed on 126 dyads, 15 mothers and 17 newborns. Positive anti-S antibodies were found in most of the vaccinated subjects, regardless of timespan between immunization and delivery (range: 7-391 days). A total of 89 of 92 vaccinated women showed a broad response to COVID-19 immunization and highly effective placental transfer, as attested by anti-S positive rates (maternal = 96.7%, cord = 96.6%). Most of our subjects had indeterminate results in an IGRA assay, preventing a conclusive evaluation of IFN-γ production. Indeed, pregnancy-related hormonal changes may influence T-cell response with an impact on IFN-γ production. Positive pregnancy and perinatal outcomes reinforce the evidence that the anti-SARS-CoV-2 immunization is effective and well-tolerated in pregnant women and also protective for the fetus/neonate, even though it was not possible to define the related IFN-γ production and role.

COVID-19 booster dose induces robust antibody response in pregnant, lactating, and nonpregnant women.

BACKGROUND: Although emerging data during the SARS-CoV-2 pandemic have demonstrated robust messenger RNA vaccine-induced immunogenicity across populations, including pregnant and lactating individuals, the rapid waning of vaccine-induced immunity and the emergence of variants of concern motivated the use of messenger RNA vaccine booster doses. Whether all populations, including pregnant and lactating individuals, will mount a comparable response to a booster dose is not known. OBJECTIVE: This study aimed to profile the humoral immune response to a COVID-19 messenger RNA booster dose in a cohort of pregnant, lactating, and nonpregnant age-matched women. STUDY DESIGN: This study characterized the antibody response against ancestral Spike and Omicron in a cohort of 31 pregnant, 12 lactating, and 20 nonpregnant age-matched controls who received a BNT162b2 or messenger RNA-1273 booster dose after primary COVID-19 vaccination. In addition, this study examined the vaccine-induced antibody profiles of 15 maternal-to-cord dyads at delivery. RESULTS: Receiving a booster dose during pregnancy resulted in increased immunoglobulin G1 levels against Omicron Spike (postprimary vaccination vs postbooster dose; P=.03). Pregnant and lactating individuals exhibited equivalent Spike-specific total immunoglobulin G1, immunoglobulin M, and immunoglobulin A levels and neutralizing titers against Omicron compared with nonpregnant women. Subtle differences in Fc receptor binding and antibody subclass profiles were observed in the immune response to a booster dose in pregnant vs nonpregnant individuals. The analysis of maternal and cord antibody profiles at delivery demonstrated equivalent total Spike-specific immunoglobulin G1 in maternal and cord blood, yet higher Spike-specific FcγR3a-binding antibodies in the cord relative to maternal blood (P=.002), consistent with the preferential transfer of highly functional immunoglobulin. Spike-specific immunoglobulin G1 levels in the cord were positively correlated with the time elapsed since receiving the booster dose (Spearman R, .574; P=.035). CONCLUSION: Study data suggested that receiving a booster dose during pregnancy induces a robust Spike-specific humoral immune response, including against Omicron. If boosting occurs in the third trimester of pregnancy, higher Spike-specific cord immunoglobulin G1 levels are achieved with greater time elapsed between receiving the booster and delivery. Receiving a booster dose has the potential to augment maternal and neonatal immunity.

Immune and pathophysiologic profiling of antenatal coronavirus disease 2019 in the GIFT cohort: A Singaporean case-control study.

COVID-19 can be severe in pregnant women, and have adverse consequences for the subsequent infant. We profiled the post-infectious immune responses in maternal and child blood as well as breast milk in terms of antibody and cytokine expression and performed histopathological studies on placentae obtained from mothers convalescent from antenatal COVID-19. Seventeen mother-child dyads (8 cases of antenatal COVID-19 and 9 healthy unrelated controls; 34 individuals in total) were recruited to the Gestational Immunity For Transfer (GIFT) study. Maternal and infant blood, and breast milk samples were collected over the first year of life. All samples were analyzed for IgG and IgA against whole SARS-CoV-2 spike protein, the spike receptor-binding domain (RBD), and previously reported immunodominant epitopes, as well as cytokine levels. The placentae were examined microscopically. The study is registered at clinicaltrials.gov under the identifier NCT04802278. We found high levels of virus-specific IgG in convalescent mothers and similarly elevated titers in newborn children. Thus, antenatal SARS-CoV-2 infection led to high plasma titers of virus-specific antibodies in infants postnatally. However, this waned within 3-6 months of life. Virus neutralization by plasma was not uniformly achieved, and the presence of antibodies targeting known immunodominant epitopes did not assure neutralization. Virus-specific IgA levels were variable among convalescent individuals' sera and breast milk. Antibody transfer ratios and the decay of transplacentally transferred virus-specific antibodies in neonatal circulation resembled that for other pathogens. Convalescent mothers showed signs of chronic inflammation marked by persistently elevated IL17RA levels in their blood. Four placentae presented signs of acute inflammation, particularly in the subchorionic region, marked by neutrophil infiltration even though > 50 days had elapsed between virus clearance and delivery. Administration of a single dose of BNT162b2 mRNA vaccine to mothers convalescent from antenatal COVID-19 increased virus-specific IgG and IgA titers in breast milk, highlighting the importance of receiving the vaccine even after natural infection with the added benefit of enhanced passive immunity.

Relationship between Anti-Spike Antibodies and Risk of SARS-CoV-2 Infection in Infants Born to COVID-19 Vaccinated Mothers.

The goal of this study was to investigate the relationship between anti-SARS-CoV-2-Spike IgG titers passively transferred to the fetus from maternal vaccination during pregnancy and timing of infant SARS-CoV-2 infection. Pregnant, vaccinated individuals (n = 105) and their infants (n = 107) were enrolled in a prospective cohort study from July 2021 to June 2022, linking infant anti-Spike IgG titer at birth to risk of SARS-CoV-2 infection in the first fifteen months of life. Cord blood sera were collected at delivery and infant sera were collected at two and six months of age. Anti-SARS-CoV-2-Spike IgG levels were quantified in cord and infant sera using an enzyme-linked immunosorbent assay. Infants were followed for SARS-CoV-2 infection through fifteen months of age. Anti-SARS-CoV-2-Spike IgG titers in infants declined significantly with increased age (p < 0.001). Infants with higher anti-Spike cord blood levels had significantly longer disease-free intervals prior to infection with SARS-CoV-2 (p = 0.027). While higher anti-Spike IgG titer at two months of age was associated with a longer interval to infection through nine months of age (p = 0.073), infant anti-Spike IgG titers by six months of age had no impact on disease-free interval. This cohort study suggests that passively transferred maternal IgG is protective against infant SARS-CoV-2 infection, with higher antibody levels at birth significantly associated with longer disease-free intervals. Infant antibodies and protection from SARS-CoV-2 infection wane significantly after six months, suggesting that vaccination is needed at this stage to optimize protection against COVID-19.

Infant immunity against viral infections is advanced by the placenta-dependent vertical transfer of maternal antibodies.

Neonatal passive immunity, derived from transplacental transfer of IgG antibodies from mother to fetus during pregnancy, can mitigate the risk for severe infections in the early postnatal period. Understanding the placenta as the gateway organ in this process, we aimed to evaluate the influence of specific factors modulating the transplacental IgG transfer rate (TPTR) in 141 mother/neonate pairs. We further evaluated the potential health advantage elicited by maternal IgG with regard to respiratory tract infections during infancy and early childhood. Data and biological samples collected within the prospective longitudinal pregnancy cohort study PRINCE (Prenatal Identification of Children's Health) were used for these analyses. We tested IgG antibody levels against seven pathogens (measles, mumps, rubella, tetanus, diphtheria, pertussis and influenza A) by ELISA and detected seropositivity in 72.6-100% of pregnant women and in 76.3-100% of their neonates, respectively. Cord blood IgG levels reached 137-160% of levels detected in maternal blood. Strikingly, assessment of TPTR for all seven antigens highlighted that TPTR strongly depends on individual placental function. Subsequent in-depth analysis of anti-influenza A IgG revealed a link between cord blood levels and uterine perfusion, measured by uterine artery pulsatility index. Moreover, higher cord blood anti-influenza A IgG levels were associated with a significantly reduced risk for respiratory tract infections during the first six months of life, indicating a high degree of cross-reactivity and possible pathogen-agnostic effects of anti-influenza A antibodies. Taken together, our data suggest that early life immunity is modulated by maternal IgG levels and individual placental features such as perfusion. Vaccination of pregnant women, i.e. against influenza, can increase neonatal antibody levels and hereby protect against early life respiratory infections. Consequently, specific guidelines should evolve in order to safeguard neonates born from pregnancies with poorer placental capacity for vertical transfer of protective antibodies.

Repertoire of Naturally Acquired Maternal Antibodies Transferred to Infants for Protection Against Shigellosis.

Shigella is the second leading cause of diarrheal diseases, accounting for >200,000 infections and >50,000 deaths in children under 5 years of age annually worldwide. The incidence of Shigella-induced diarrhea is relatively low during the first year of life and increases substantially, reaching its peak between 11 to 24 months of age. This epidemiological trend hints at an early protective immunity of maternal origin and an increase in disease incidence when maternally acquired immunity wanes. The magnitude, type, antigenic diversity, and antimicrobial activity of maternal antibodies transferred via placenta that can prevent shigellosis during early infancy are not known. To address this knowledge gap, Shigella-specific antibodies directed against the lipopolysaccharide (LPS) and virulence factors (IpaB, IpaC, IpaD, IpaH, and VirG), and antibody-mediated serum bactericidal (SBA) and opsonophagocytic killing antibody (OPKA) activity were measured in maternal and cord blood sera from a longitudinal cohort of mother-infant pairs living in rural Malawi. Protein-specific (very high levels) and Shigella LPS IgG were detected in maternal and cord blood sera; efficiency of placental transfer was 100% and 60%, respectively, and had preferential IgG subclass distribution (protein-specific IgG1 > LPS-specific IgG2). In contrast, SBA and OPKA activity in cord blood was substantially lower as compared to maternal serum and varied among Shigella serotypes. LPS was identified as the primary target of SBA and OPKA activity. Maternal sera had remarkably elevated Shigella flexneri 2a LPS IgM, indicative of recent exposure. Our study revealed a broad repertoire of maternally acquired antibodies in infants living in a Shigella-endemic region and highlights the abundance of protein-specific antibodies and their likely contribution to disease prevention during the first months of life. These results contribute new knowledge on maternal infant immunity and target antigens that can inform the development of vaccines or therapeutics that can extend protection after maternally transferred immunity wanes.

Transplacental Respiratory Syncytial Virus and Influenza Virus Antibody Transfer in Alaska Native and Seattle Mother-Infant Pairs.

BACKGROUND: Alaska Native (AN) infants are at risk for severe disease due to respiratory syncytial virus (RSV) and influenza. Maternal immunization protects young infants through transplacental antibody transfer. RSV- and influenza-specific transplacental antibody transfer in mother-infant pairs has not previously been evaluated in the AN population. METHODS: Serum samples collected during pregnancy and at birth from AN mother-infant pairs in the Yukon-Kuskokwim Delta region (YKD) of Alaska (2000-2011; n = 75) and predominantly white pairs in Seattle, Washington (2014-2016; n = 57), were tested for RSV and influenza antibody using a microneutralization and hemagglutination inhibition assay, respectively, and compared between sites. RESULTS: Mean RSV antibody concentrations in pregnant women in YKD and Seattle were similar (log2 RSV antibody 10.6 vs 10.7, P = .86), but cord blood RSV antibody concentrations were significantly lower in infants born to mothers in YKD compared with Seattle (log2 RSV antibody 11.0 vs 12.2, P < .001). Maternal and cord blood influenza antibody concentrations were lower for women and infants in YKD compared with Seattle for all 4 influenza antigens tested (all P < .05). The mean cord to maternal RSV antibody transfer ratio was 1.15 (standard deviation [SD], 0.13) in mother-infant pairs in Seattle compared with 1.04 (SD, 0.08) in YKD. Mean cord blood to maternal antibody transfer ratios for influenza antigens ranged from 1.22 to 1.42 in Seattle and from 1.05 to 1.59 in YKD. CONCLUSIONS: Though the transplacental antibody transfer ratio was high (>1.0) for both groups, transfer ratios for RSV antibody were significantly lower in AN mother-infant pairs. Further studies are needed to elucidate the impact of lower transplacental antibody transfer on infant disease risk in rural Alaska.Alaska Native and continental US mother-infant pairs have high transplacental antibody transfer ratios (>1.0) for influenza and respiratory syncytial virus, but anti-respiratory syncytial virus antibody levels are significantly lower in Alaska Native pairs than in those from the continental US.

Immunogenicity of influenza vaccines administered to pregnant women in randomized clinical trials in Mali and South Africa.

BACKGROUND: A key consideration for expanding recommendations for influenza vaccination is a robust assessment of immunogenicity and efficiency of transplacental antibody transfer after maternal vaccination. METHODS: We pooled data from two trials of maternal influenza vaccination to analyze vaccine immunogenicity with more power than either trial had alone. We compared hemagglutination-inhibition (HAI) titers and titer factor change for women and their infants between trial arms using t-tests; maternal and infant putative seroprotective titers (HAI ≥ 1:40) within each trial arm and maternal seroconversion between trial arms using exact tests; and transplacental antibody transfer between trial arms using t-tests. We used marginal linear models and generalized estimating equations to examine the impact of time between maternal vaccination and delivery on transplacental antibody transfer, infant titers, and infant seroprotection. RESULTS: For all vaccine components (A/H1N1, A/H3N2, and Type B), >80% of vaccinated women had seroprotective titers, >60% of them seroconverted, and >50% of their infants were born with seroprotective titers. These immunogenicity outcomes occurred more often in vaccine recipients and their infants than in controls. No difference in efficiency of transplacental antibody transfer was observed between vaccine recipients and controls. CONCLUSIONS: Our results provide robust support for further expansion of maternal influenza vaccination recommendations. CLINICAL TRIALS REGISTRATION: NCT01430689 and NCT01306669.

Evaluation of respiratory syncytial virus IgG antibody dynamics in mother-infant pairs cohort.

RSV is one of the most important agents of lower respiratory infections in childhood. In this study, anti-RSV antibody levels in mother-infant pairs and factors related to antibody transfer ratio were investigated. One hundred and twenty-seven women that had term babies and their babies and 84 mother-infant pairs of them who continued the study after 6 months were enrolled. Anti-RSV IgG antibodies of the mothers and infants were positive in 46.5% and 61.5%, respectively. At the sixth month, anti-RSV antibodies were negative in all infants. Median of the anti-RSV antibody levels of the mothers and infants at birth were 12.08 IU/ml (1.21-119.27) and 13.78 IU/ml (3.99-108.6), respectively. There was a significant correlation between anti-RSV antibody levels of mothers and infants at birth (p: 0.0001, r: 0.667) and anti-RSV antibody levels of infants at birth and at 6th month (p: 0.0001, r: 0.343). Median ratio of infant and mother antibody levels was 1.22 (0.14-6.05). Median ratio that was detected in appropriate for gestational age infants was significantly higher than in small for gestational age or large for gestational age infants. In this study, the significant positive correlation between maternal antibody levels and infants' antibody levels at birth suggests that maternal vaccination strategies may be logical. We showed that antibody transfer rate was highest in appropriate for gestational age infants. It should be kept in mind that maternal vaccination strategies may be less effective in small for gestational age and large for gestational age infants.

Immunogenicity and safety of a quadrivalent inactivated influenza vaccine in pregnant women: a randomized, observer-blind trial.

Vaccination against influenza during pregnancy provides direct protection to pregnant women and indirect protection to their infants. Trivalent inactivated influenza vaccines (IIV3s) are safe and effective during pregnancy, but quadrivalent inactivated influenza vaccines (IIV4s) have not been evaluated in pregnant women and their infants. Here, we report the results of a randomized phase IV study to evaluate the immunogenicity and safety of IIV4 vs. IIV3 in pregnant women. Participants aged ≥18 years at weeks 20 to 32 of gestation were randomly assigned in a 2:1 ratio to receive a single dose of IIV4 (n = 230) or IIV3 (n = 116). Between baseline and 21 days after vaccination, hemagglutination inhibition (HAI) antibody titers increased in both groups by similar magnitudes for the two influenza A strains and single B strain common to IIV4 and IIV3. For the additional B strain in IIV4, HAI titers were higher in IIV4 recipients than IIV3 recipients (post-/pre-vaccination geometric mean titer ratio, 6.3 [95% CI: 5.1 - 7.7] vs. 3.4 [95% CI: 2.7 - 4.3]). At delivery, in both groups, HAI antibody titers for all strains were 1.5 - 1.9-fold higher in umbilical cord blood than in maternal blood, confirming active transplacental antibody transfer. Rates of solicited and unsolicited vaccine-related adverse events in mothers were similar between the two groups. Live births were reported for all participants and there were no vaccine-related adverse events in newborns. These results suggest IIV4 is as safe and immunogenic as IIV3 in pregnant women, and that maternal immunization with IIV4 should protect newborns against influenza via passively acquired antibodies.

Reduced Transplacental Transfer of Antimalarial Antibodies in Kenyan HIV-Exposed Uninfected Infants.

BACKGROUND: Altered neonatal immune responses may contribute to the increased morbidity observed in HIV-exposed but uninfected (HEU) infants compared with HIV-unexposed uninfected (HUU) infants. We sought to examine the effects of prenatal HIV and malaria exposure on maternal and neonatal plasma cytokine profiles and transplacental antibody transfer. METHODS: Forty-nine HIV+ and 50 HIV- women and their HIV-uninfected neonate pairs from Kenya were assessed. All HIV+ mothers received combination antiretroviral therapy. Maternal plasma and cord blood plasma samples at delivery were tested for 12 cytokines, total IgG, and IgG specific to 4 vaccine antigens and 14 Plasmodium falciparum antigens. RESULTS: HIV+ mothers had lower levels of all 12 plasma cytokines at delivery compared with HIV- mothers, but there were no differences between HEU and HUU neonates. There were no differences in the cord-to-maternal ratios (CMRs) of vaccine-specific IgG between HIV+/HEU and HIV-/HUU maternal-neonate pairs. HIV+/HEU maternal-neonate pairs had significantly lower CMRs for 3 antimalarial IgGs-merozoite surface protein 9, circumsporozoite protein, and erythrocyte binding antigen 181-which remained statistically significant after adjustment for malaria in pregnancy. CONCLUSIONS: In a cohort of optimally treated HIV-infected pregnant women, maternal HIV infection was associated with reduced transplacental transfer of antimalarial antibodies.

Who's the Target: Mother or Baby?

Maternal immunization for prevention of morbidity and mortality of pregnant women and their neonates due to infectious diseases is ongoing worldwide. The complexity of vaccine research and development in this population is challenging. Not only do vaccines for pregnant women require evidence of immunogenicity, potency, stability, and limited reactogenicity, they must also provide efficacy in decreasing morbidity for the pregnant woman, her fetus, and the neonate, demonstrate safety or lack of evidence of harm, and offer benefit or potential benefit of vaccination during pregnancy. Since the 19th century, evidence of protective effects of vaccination during pregnancy has been documented. Pandemic influenza and pertussis outbreaks in recent years have affected a paradigm shift in vaccine research and development as well as current policy regarding immunization in pregnancy. Studies of the immune system in pregnant women and neonates have shown that immune changes associated with pregnancy in women do not interfere with maternal vaccine responses, multiple factors are important in transplacental transfer of antibodies, and maternal antibodies are beneficial to neonates. In recent years, guidelines have been developed by expert panels to help design studies for maternal vaccinations and for harmonization of data collection, analysis, and adverse event reporting. Further research into maternal and neonatal immunology, transplacental antibody transfer, and epidemiology of diseases is needed, especially as new vaccines to respiratory syncytial virus, cytomegalovirus, and Group B streptococcus are developed. Maternal vaccinations have the potential to change the epidemiology of infectious diseases in reproductive health and pediatrics and may lead to new clinical applications to improve global maternal and neonatal health.

Transplacental transfer of maternal respiratory syncytial virus (RSV) antibody and protection against RSV disease in infants in rural Nepal.

BACKGROUND: Respiratory syncytial virus (RSV) is the most important viral cause of pneumonia in children. RSV-specific antibody (ab) protects infants from disease, and may be increased by a potential strategy of maternal RSV vaccination. OBJECTIVES: To describe the effect of RSV antibody on RSV infection risk in infants in a resource-limited setting. STUDY DESIGN: In a prospective study in Nepal, women were enrolled during pregnancy and maternal and infant cord blood were collected at birth. Weekly surveillance for respiratory illness was performed from birth to 180days. Nasal swabs were tested for RSV by PCR and serum was tested using an RSV antibody microneutralization assay. Antibody concentrations at time of RSV infection were estimated based on a decay rate of 0.026 log2/day. RESULTS: Cord:maternal RSV antibody transfer ratio was 1.03 (0.88-1.19), with RSV antibody concentration of log2 11.3 and log2 11.7 in 310 paired maternal and infant samples, respectively. Cord blood RSV antibody was log2 12.1 versus 11.6 in those with or without RSV infection (P=0.86). Among infants with RSV infection, estimated RSV antibody concentration at time of infection did not differ in infants with upper (n=8; log2 10.7) versus lower respiratory tract infection (n=21; log2 9.8; P=0.37). Cord blood RSV antibody concentrations did not correlate with age at primary RSV infection (R=0.11; P=0.57). CONCLUSIONS: Transplacental transfer of RSV antibody from mother to the fetus was highly efficient in mother-infant pairs in rural Nepal, though higher antibody concentrations were not protective against earlier or more severe RSV infection in infants.

A Phase 2 randomized, observer-blind, placebo-controlled, dose-ranging trial of aluminum-adjuvanted respiratory syncytial virus F particle vaccine formulations in healthy women of childbearing age.

OBJECTIVE: Respiratory syncytial virus (RSV) causes significant morbidity and mortality in infants. We are developing an RSV fusion (F) protein nanoparticle vaccine for immunization of third trimester pregnant women to passively protect infants through transfer of RSV-specific maternal antibodies. The present trial was performed to assess the immunogenicity and safety of several formulations of RSV F vaccine in 1-dose or 2-dose schedules. METHODS: Placebo, or vaccine with 60µg or 120µg RSV F protein and 0.2, 0.4, or 0.8mg aluminum, were administered intramuscularly on Days 0 and 28 to healthy women 18-35years old. Immunogenicity was assessed from Days 0 through 91 based on anti-F IgG and palivizumab-competitive antibody (PCA) by ELISA, and RSV A and B neutralizing antibodies by microneutralization (MN) assay. Solicited adverse events were collected through Day 7 and unsolicited adverse events through Day 91. RESULTS: All formulations were well-tolerated, with no treatment-related serious adverse events. Anti-F IgG and PCA responses were correlated and increased after both doses, while MN increased significantly only after the first dose, then plateaued. The timeliest and most robust antibody responses followed one dose of 120µg RSV F protein and 0.4mg aluminum, but persistence through 91days was modestly (∼25%) superior following two doses of 60µg RSV F protein and 0.8mg aluminum. Western blot analysis showed RSV infections in active vaccinees were reduced by 52% overall (p=0.009 overall) over the Day 0 through 90 period. CONCLUSIONS: RSV F nanoparticle vaccine formulations were well tolerated and immunogenic. The optimal combination of convenience and rapid response for immunization in the third trimester occurred with 120µg RSV F and 0.4mg aluminum, which achieved peak immune responses in 14days and sufficient persistence through 91days to allow for passive transfer of IgG antibodies to the fetus. NCT01960686.

Modeling maternal fetal RSV F vaccine induced antibody transfer in guinea pigs.

BACKGROUND: Protection of newborns and young infants against RSV disease via maternal immunization mediated by transplacental transfer of antibodies is under evaluation in third-trimester pregnant women with the RSV recombinant F nanoparticle vaccine (RSV F vaccine). Since the hemichorial placental architecture in guinea pigs and humans is similar, the guinea pig model was employed to assess RSV F vaccine immunogenicity in pregnant sows and to compare RSV-specific maternal antibody levels in their pups. METHODS: Thirty (30) presumptive pregnant guinea pigs were immunized on gestational day 25 and 46 with placebo (PBS), 30µg RSV F, or 30µg RSV F+400µg aluminum phosphate. Sera at delivery/birth (sows/pups) and 15 and 30 days post-partum (pups) were analyzed for the presence of anti-F IgG, palivizumab-competitive antibody (PCA) and RSV/A microneutralization (MN). RESULTS: The rates of pregnancy and stillbirth were similar between controls and vaccinees. The vaccine induced high levels of anti-F IgG, PCA and MN in sows, with the highest levels observed in adjuvanted vaccinees. Placental transfer to pups was proportional to the maternal antibody levels, with concentration effects observed for all immune measures. CONCLUSIONS: The RSV F vaccine was safe and immunogenic in pregnant guinea pigs and supported robust transplacental antibody transfer to their pups. Relative concentration of antibodies in the pups was observed even in the presence of high levels of maternal antibody. Guinea pigs may be an important safety and immunogenicity model for preclinical assessment of candidate vaccines for maternal immunization.

Kinetics of Hemagglutination-Inhibiting Antibodies Following Maternal Influenza Vaccination Among Mothers With and Those Without HIV Infection and Their Infants.

BACKGROUND: We evaluated the immunogenicity of trivalent inactivated influenza vaccine (IIV3) in pregnant women with and those without human immunodeficiency virus (HIV) infection and the persistence of hemagglutination-inhibiting antibodies in mothers and infants. METHODS: Antibodies were measured before vaccination, 1 month after vaccination, at delivery, and at postpartum week 24 in mothers and within 1 week of birth and at 8, 16, and 24 weeks of age in infants. RESULTS: We enrolled 98 HIV-uninfected and 100 HIV-infected pregnant women, including 93% with a CD4(+) T-cell count of ≥ 200 cells/µL. Compared with HIV-uninfected women, HIV-infected women had lower seroconversion rates (ranging from 63%-92% vs 36%-40%), lower antibody titers through postpartum week 24, and overlapping antibody half-lives (ranging from 106-121 vs 87-153 days). Infant titers were lower than the maternal titers within 1 week of delivery, regardless of vaccine strain and HIV exposure status. Compared with HIV-unexposed infants, HIV-exposed infants had a similar transplacental influenza virus antibody transfer ratio, lower titers, and a lower frequency of titers ≥ 1:40 (ranging from 82%-95% vs 43%-79%) at birth and higher antibody half-lives (ranging from 43-45 vs 56-65 days). CONCLUSIONS: Compared with HIV-uninfected pregnant women, HIV-infected pregnant women had lower antibody responses and persistence. Compared with HIV-unexposed infants, HIV-exposed infants had lower antibody levels at birth but similar antibody levels after 8 weeks of life. Early IIV3 administration during pregnancy did not decrease antibody titers among infants at birth.