Longitudinal humoral analysis in RSV-infected infants identifies pre-existing RSV strain-specific G and evolving cross-reactive F antibodies.

Respiratory syncytial virus (RSV) is among the most common causes of lower respiratory tract infection (LRTI) and hospitalization in infants. However, the mechanisms of immune control in infants remain incompletely understood. Antibody profiling against attachment (G) and fusion (F) proteins in children less than 2 years of age, with mild (outpatients) or severe (inpatients) RSV disease, indicated substantial age-dependent differences in RSV-specific immunity. Maternal antibodies were detectable for the first 3 months of life, followed by a long window of immune vulnerability between 3 and 6 months and a rapid evolution of FcγR-recruiting immunity after 6 months of age. Acutely ill hospitalized children exhibited lower G-specific antibodies compared with healthy controls. With disease resolution, RSV-infected infants generated broad functional RSV strain-specific G-responses and evolved cross-reactive F-responses, with minimal maternal imprinting. These data suggest an age-independent RSV G-specific functional humoral correlate of protection, and the evolution of RSV F-specific functional immunity with disease resolution.

Pregnancy enables antibody protection against intracellular infection.

Adaptive immune components are thought to exert non-overlapping roles in antimicrobial host defence, with antibodies targeting pathogens in the extracellular environment and T cells eliminating infection inside cells1,2. Reliance on antibodies for vertically transferred immunity from mothers to babies may explain neonatal susceptibility to intracellular infections3,4. Here we show that pregnancy-induced post-translational antibody modification enables protection against the prototypical intracellular pathogen Listeria monocytogenes. Infection susceptibility was reversed in neonatal mice born to preconceptually primed mothers possessing L. monocytogenes-specific IgG or after passive transfer of antibodies from primed pregnant, but not virgin, mice. Although maternal B cells were essential for producing IgGs that mediate vertically transferred protection, they were dispensable for antibody acquisition of protective function, which instead required sialic acid acetyl esterase5 to deacetylate terminal sialic acid residues on IgG variable-region N-linked glycans. Deacetylated L. monocytogenes-specific IgG protected neonates through the sialic acid receptor CD226,7, which suppressed IL-10 production by B cells leading to antibody-mediated protection. Consideration of the maternal-fetal dyad as a joined immunological unit reveals protective roles for antibodies against intracellular infection and fine-tuned adaptations to enhance host defence during pregnancy and early life.

Maternal-driven immune education in offspring.

Maternal environmental exposures, particularly during gestation and lactation, significantly influence the immunological development and long-term immunity of offspring. Mammalian immune systems develop through crucial inputs from the environment, beginning in utero and continuing after birth. These critical developmental windows are essential for proper immune system development and, once closed, may not be reopened. This review focuses on the mechanisms by which maternal exposures, particularly to pathogens, diet, and microbiota, impact offspring immunity. Mechanisms driving maternal-offspring immune crosstalk include transfer of maternal antibodies, changes in the maternal microbiome and microbiota-derived metabolites, and transfer of immune cells and cytokines via the placenta and breastfeeding. We further discuss the role of transient maternal infections, which are common during pregnancy, in providing tissue-specific immune education to offspring. We propose a "maternal-driven immune education" hypothesis, which suggests that offspring can use maternal encounters that occur during a critical developmental window to develop optimal immune fitness against infection and inflammation.

Immunity in the Very Young: Challenges and Opportunities.

Immunity in early life encompasses the delicate interphase at the maternal-fetal stage, as well as rapid development and adaptation that occur as the newborn transitions from the protected maternal environment to functioning in the outside world. Understanding the forces that shape immunity in the very young and that lay the groundwork for an effective adult immune system holds both questions and promise.

Potential for Maternally Administered Vaccine for Infant Group B Streptococcus.

BACKGROUND: Natural history studies have correlated serotype-specific anti-capsular polysaccharide (CPS) IgG in newborns with a reduced risk of group B streptococcal disease. A hexavalent CPS-cross-reactive material 197 glycoconjugate vaccine (GBS6) is being developed as a maternal vaccine to prevent invasive group B streptococcus in young infants. METHODS: In an ongoing phase 2, placebo-controlled trial involving pregnant women, we assessed the safety and immunogenicity of a single dose of various GBS6 formulations and analyzed maternally transferred anti-CPS antibodies. In a parallel seroepidemiologic study that was conducted in the same population, we assessed serotype-specific anti-CPS IgG concentrations that were associated with a reduced risk of invasive disease among newborns through 89 days of age to define putative protective thresholds. RESULTS: Naturally acquired anti-CPS IgG concentrations were associated with a reduced risk of disease among infants in the seroepidemiologic study. IgG thresholds that were determined to be associated with 75 to 95% reductions in the risk of disease were 0.184 to 0.827 µg per milliliter. No GBS6-associated safety signals were observed among the mothers or infants. The incidence of adverse events and of serious adverse events were similar across the trial groups for both mothers and infants; more local reactions were observed in the groups that received GBS6 containing aluminum phosphate. Among the infants, the most common serious adverse events were minor congenital anomalies (umbilical hernia and congenital dermal melanocytosis). GBS6 induced maternal antibody responses to all serotypes, with maternal-to-infant antibody ratios of approximately 0.4 to 1.3, depending on the dose. The percentage of infants with anti-CPS IgG concentrations above 0.184 µg per milliliter varied according to serotype and formulation, with 57 to 97% of the infants having a seroresponse to the most immunogenic formulation. CONCLUSIONS: GBS6 elicited anti-CPS antibodies against group B streptococcus in pregnant women that were transferred to infants at levels associated with a reduced risk of invasive group B streptococcal disease. (Funded by Pfizer and the Bill and Melinda Gates Foundation; C1091002 ClinicalTrials.gov number, NCT03765073.).

Breast Milk-Derived Antibodies Impair Vaccine Immunity in Suckling Mice.

Breast milk confers multiple benefits to the neonate, including passive immunity against multiple microorganisms via Abs. However, it remains unclear whether breast milk-derived Abs affect vaccine-induced immunity in the neonate. We evaluated in C57BL/6 and BALB/c mice whether breastfeeding from an mRNA-SARS-CoV-2-vaccinated dam affects vaccine-induced immunity in neonate mice. Using an experimental model that allows the distinction of maternal Abs and neonate Abs based on their allotype, we show that breastfeeding from an immune dam is associated with reduced vaccine immunity in the neonate. Importantly, mice that breastfed from an immune dam showed reduced numbers of plasma cells after vaccination, relative to mice that breastfed from a naive dam. Our subsequent studies using an mRNA-luciferase reporter system show that passive transfer of Abs through breastfeeding accelerates the clearance of vaccine Ag in suckling mice, resulting in reduced Ag availability. Altogether, maternal Abs transferred through breast milk can protect against infectious microorganisms, but they may also interfere with the neonate's response to vaccination by accelerating the clearance of vaccine Ag. These findings are important for understanding the effects of maternal Abs on the neonate's response to vaccines and may provide insights for improving neonatal vaccines.

Microbiota-targeted maternal antibodies protect neonates from enteric infection.

Although maternal antibodies protect newborn babies from infection1,2, little is known about how protective antibodies are induced without prior pathogen exposure. Here we show that neonatal mice that lack the capacity to produce IgG are protected from infection with the enteric pathogen enterotoxigenic Escherichia coli by maternal natural IgG antibodies against the maternal microbiota when antibodies are delivered either across the placenta or through breast milk. By challenging pups that were fostered by either maternal antibody-sufficient or antibody-deficient dams, we found that IgG derived from breast milk was crucial for protection against mucosal disease induced by enterotoxigenic E. coli. IgG also provides protection against systemic infection by E. coli. Pups used the neonatal Fc receptor to transfer IgG from milk into serum. The maternal commensal microbiota can induce antibodies that recognize antigens expressed by enterotoxigenic E. coli and other Enterobacteriaceae species. Induction of maternal antibodies against a commensal Pantoea species confers protection against enterotoxigenic E. coli in pups. This role of the microbiota in eliciting protective antibodies to a specific neonatal pathogen represents an important host defence mechanism against infection in neonates.

Hybrid Immunity to SARS-CoV-2 During Pregnancy Provides More Durable Infant Antibody Responses Compared to Natural Infection Alone.

BACKGROUND: Hybrid immunity (infection plus vaccination) may increase maternally derived SARS-CoV-2 antibody responses and durability versus infection alone. METHODS: Prospective cohort of pregnant participants with prior SARS-CoV-2 infection (anti-nucleocapsid IgG, RT-PCR, or antigen positive) and their infants had blood collected in pregnancy, at delivery/birth, and postpartum tested for anti-spike (anti-S) IgG and neutralizing antibodies (neutAb). RESULTS: Among 107 participants at enrollment, 40% were unvaccinated and 60% were vaccinated (received ≥1 dose); 102 had previous SARS-CoV-2 infection in pregnancy (median, 19 weeks' gestation); 5 were diagnosed just prior to pregnancy (median, 8 weeks). At delivery, fewer unvaccinated participants (87% anti-S IgG+, 86% neutAb) and their infants (86% anti-S IgG+, 75% neutAb) had anti-S IgG+ or neutAb compared to vaccinated participants and their infants (100%, P ≤ .01 for all). By 3-6 months postpartum, 50% of infants of unvaccinated participants were anti-S IgG+ and 14% had neutAb, versus 100% among infants of vaccinated participants (all P < .01), with lower median antibody responses (anti-S IgG log10 1.95 vs 3.84 AU/mL, P < .01; neutAb log10 1:1.34 vs 1:3.20, P = .11). CONCLUSIONS: In pregnant people with prior SARS-CoV-2, vaccination before delivery provided more durable maternally derived antibody responses than infection alone in infants through 6 months.

SARS-CoV-2 infection vs. vaccination during pregnancy: the placenta leads the way.

PURPOSE OF REVIEW: To understand the characteristics and determinants of transplacental antibody transfer against SARS-CoV-2 and to compare the differences between SARS-CoV-2 infection and vaccination. RECENT FINDINGS: The need for information during the COVID-19 pandemic and the exclusion of pregnant women from randomized clinical trials have led to a vast amount of clinical data primarily based on observational studies with diverse design and sample analyses that yield variable results. This review aims to critically and comprehensively integrate the relevant knowledge related to transplacental transfer of antibodies against SARS-CoV-2, emphasizing the differences between infection and vaccination. SUMMARY: Passive immunization is key to conferring protection to the infant during their first months of life. Understanding the mechanisms of transplacental antibody transfer during SARS-CoV-2 infection and vaccination, and their associated protection will allow optimizing the implementation of well tolerated and effective preventive strategies for both pregnant women and infants.

Immune response induced by a Streptococcus suis multi-serotype autogenous vaccine used in sows to protect post-weaned piglets.

Streptococcus suis is a bacterial pathogen that causes important economic losses to the swine industry worldwide. Since there are no current commercial vaccines, the use of autogenous vaccines applied to gilts/sows to enhance transfer of passive immunity is an attractive alternative to protect weaned piglets. However, there is no universal standardization in the production of autogenous vaccines and the vaccine formulation may be highly different among licenced manufacturing laboratories. In the present study, an autogenous vaccine that included S. suis serotypes 2, 1/2, 5, 7 and 14 was prepared by a licensed laboratory and administrated to gilts using a three-dose program prior to farrowing. The antibody response in gilts as well as the passive transfer of antibodies to piglets was then evaluated. In divergence with previously published data with an autogenous vaccine produced by a different company, the increased response seen in gilts was sufficient to improve maternal antibody transfer to piglets up to 5 weeks of age. However, piglets would still remain susceptible to S. suis disease which often appears during the second part of the nursery period. Vaccination did not affect the shedding of S. suis (as well as that of the specific S. suis serotypes included in the vaccine) by either gilts or piglets. Although all antibiotic treatments were absent during the trial, the clinical protective effect of the vaccination program with the autogenous vaccine could not be evaluated, since limited S. suis cases were present during the trial, confirming the need for a complete evaluation of the clinical protection that must include laboratory confirmation of the aetiological agent involved in the presence of S. suis-associated clinical signs. Further studies to evaluate the usefulness of gilt/sow vaccination with autogenous vaccines to protect nursery piglets should be done.

Spray vaccination with a Newcastle disease virus (NDV)-vectored infectious laryngotracheitis (ILT) vaccine protects commercial chickens from ILT in the presence of maternally-derived antibodies.

Infectious laryngotracheitis (ILT) poses a significant threat to the poultry industry, and vaccines play an important role in protection. However, due to the increasing scale of poultry production, there is an urgent need to develop vaccines that are suitable for convenient immunization methods such as spraying. Previous studies have shown that Newcastle disease virus (NDV)-ILT vaccines administered via intranasal and intraocular routes to commercial chickens carrying maternally-derived antibodies (MDAs) are still protective against ILT. In this study, a recombinant NDV (rNDV) was generated to express infectious laryngotracheitis virus (ILTV) glycoprotein B (gB), named rLS-gB, based on a full-length cDNA clone of the LaSota strain. The protective effect of different doses of rLS-gB administered by spray vaccination to commercial chickens at 1 d of age (doa) was evaluated. The chickens were exposed to 160-µm aerosol particles for 10 min for spray vaccination, and no adverse reactions were observed after vaccination. Despite the presence of anti-NDV MDAs and anti-ILTV MDAs in chickens, the ILTV- and NDV-specific antibody titres were significantly greater in the vaccinated groups than in the unvaccinated group. After challenge with a virulent ILTV strain, no clinical signs were observed in the 107 EID50/ml group compared to the other groups. Furthermore, vaccination with 107 EID50/ml rLS-gB significantly reduced the ILTV viral load and ameliorated gross and microscopic lesions in the trachea of chickens. Overall, these results suggested that rLS-gB is a safe and efficient candidate spray vaccine for ILT and is especially suitable for scaled chicken farms.

A field comparison study of two vaccine protocols against Erysipelothrix rhusiopathiae in two types of swine breeds in Spain.

Erysipelas still causes large economic losses to pig industry. Maternal immunity is critical to prevent erysipelas in young animals, thus, intensive vaccination protocols or practices focused on the improvement of the maternally derived immunity could provide substantial benefits. The present study evaluates potential changes in antibodies levels in sows and their offspring using two types of tests (commercial ELISA, Ingenasa or rSpaA415 ELISA) when two different vaccination programs (before farrowing or after farrowing) against Erysipelothrix rhusiopathiae were applied to sows from Iberian (A) or conventional Large White-Landrace (B) pig farms. The results showed a statistical correlation between titers found in sows and their one-week old piglets in both tests. The overall mean of (log) antibody titers in farm B measured by the commercial ELISA test was significantly higher in pre-farrowing vaccinated sows compared to the post-farrowing vaccine protocol (p = 0.0278). Additionally, using the rSpaA415 ELISA test, the overall mean of (log) antibody titers was significantly higher in pre-farrowing sows (p = 0.0056) compared to sows following post-farrowing vaccine protocol (p = 0.0003) or non- vaccinated sows. None of the above-mentioned differences were found in farm A. The overall mean of (log) antibody titers in piglets from the pre-farrowing vaccination protocol was significantly higher than piglets from the post-farrowing vaccination protocol in farm A (p = 0.0059; rSpaA415 ELISA) and farm B (p = 0.0168 and p = 0.0098 for the commercial and rSpaA415 ELISA data, respectively). Additionally, higher proportion of piglets from pre-farrowing vaccinated sows remained seropositive during the post-weaning period (days 42 to 84) compared to piglets from non-vaccinated or post-farrowing vaccinated groups in both farms A and B.

Regulation of neonatal IgA production by the maternal microbiota.

Infants are prone to enteric infections due to an underdeveloped immune system. The maternal microbiota, through shaping the neonatal microbiota, helps establish a strong immune system in infants. We and others have observed the phenomenon of enhanced early neonatal immunoglobulin A (IgA) production in preweaning immunocompetent mice nursed by immunodeficient dams. Here, we show that this enhancement of IgA in neonates results from maternally derived microbiota. In addition, we have found that the neonatal IgA production can be induced by Lactobacillus reuteri, which is enriched in the milk of immunodeficient dams. Moreover, we show that while the production of neonatal IgA is dependent on neonatal T cells, the immunodeficient maternal microbiota-mediated enhancement of neonatal IgA has a T cell-independent component. Indeed, this enhancement may be dependent on type 3 innate lymphoid cells in the neonatal small intestinal lamina propria. Interestingly, maternal microbiota-induced neonatal IgA does not cross-react with common enteric pathogens. Future investigations will determine the functional consequences of having this extra IgA.

ELF3 activated by a superenhancer and an autoregulatory feedback loop is required for high-level HLA-C expression on extravillous trophoblasts.

HLA-C arose during evolution of pregnancy in the great apes 10 to 15 million years ago. It has a dual function on placental extravillous trophoblasts (EVTs) as it contributes to both tolerance and immunity at the maternal-fetal interface. The mode of its regulation is of considerable interest in connection with the biology of pregnancy and pregnancy abnormalities. First-trimester primary EVTs in which HLA-C is highly expressed, as well as JEG3, an EVT model cell line, were employed. Single-cell RNA-seq data and quantitative PCR identified high expression of the transcription factor ELF3 in those cells. Chromatin immunoprecipitation (ChIP)-PCR confirmed that both ELF3 and MED1 bound to the proximal HLA-C promoter region. However, binding of RFX5 to this region was absent or severely reduced, and the adjacent HLA-B locus remained closed. Expression of HLA-C was inhibited by ELF3 small interfering RNAs (siRNAs) and by wrenchnolol treatment. Wrenchnolol is a cell-permeable synthetic organic molecule that mimics ELF3 and is relatively specific for binding to ELF3's coactivator, MED23, as our data also showed in JEG3. Moreover, the ELF3 gene is regulated by a superenhancer that spans more than 5 Mb, identified by assay for transposase-accessible chromatin using sequencing (ATAC-seq), as well as by its sensitivity to (+)-JQ1 (inhibitor of BRD4). ELF3 bound to its own promoter, thus creating an autoregulatory feedback loop that establishes expression of ELF3 and HLA-C in trophoblasts. Wrenchnolol blocked binding of MED23 to ELF3, thus disrupting the positive-feedback loop that drives ELF3 expression, with down-regulation of HLA-C expression as a consequence.

Serum concentrations of selenium, copper, and zinc in neonatal foals: Influence of failure of passive transfer and age-related changes.

Background: An adequate supply of trace elements is very important for equine neonates, as deficiencies can lead to health problems and even death. Objective: This study investigated serum concentrations of selenium (Se), copper (Cu), and zinc (Zn) in neonatal foals up to the 8th day of life. The influences of disease, age, and failure of passive transfer (FPT) on these concentrations were analyzed. Animals and procedure: Serum concentrations of Se, Cu, and Zn were determined from blood samples of 93 foals by means of inductively coupled plasma mass spectrometry. The foals were divided into 2 groups based on health status: clinically sick (n = 51) and clinically healthy (n = 42). The latter group was further divided into foals with FPT (n = 20) and those without (n = 22). Results: Mean serum concentrations for Se, Cu, and Zn were 60 ± 40 µg/L, 0.25 ± 0.22 mg/L, and 605 ± 285 µg/L, respectively. A significant influence of age on serum Cu concentration was observed (P < 0.0001). No differences were observed between any of the serum concentrations in clinically sick and clinically healthy foals on the 1st day of life. The FPT status was not associated with reduced serum concentrations of Se, Cu, or Zn. Conclusion and clinical relevance: It is not necessary to supplement trace elements in all foals with FPT.

Concentrations sériques de sélénium, de cuivre et de zinc chez les poulains nouveau-nés : influence de l'échec du transfert passif et des changements liés à l'âge. Contexte: Un apport suffisant en oligo-éléments est très important pour les nouveau-nés équins, car des carences peuvent entraîner des problèmes de santé, voire la mort. Objectif: Cette étude a examiné les concentrations sériques de sélénium (Se), de cuivre (Cu) et de zinc (Zn) chez les poulains nouveau-nés jusqu'au 8ème jour de vie. Les influences de maladies, de l'âge et de l'échec du transfert passif (FPT) sur ces concentrations ont été analysées. Animaux et procédure: Les concentrations sériques de Se, Cu et Zn ont été déterminées à partir d'échantillons de sang de 93 poulains au moyen d'une spectrométrie de masse à plasma à couplage inductif. Les poulains ont été divisés en 2 groupes en fonction de leur état de santé: cliniquement malades (n = 51) et cliniquement sains (n = 42). Ce dernier groupe a été divisé en poulains avec FPT (n = 20) et ceux sans (n = 22). Résultats: Les concentrations sériques moyennes de Se, Cu et Zn étaient respectivement de 60 ± 40 µg/L, 0,25 ± 0,22 mg/L et 605 ± 285 µg/L. Une influence significative de l'âge sur la concentration sérique de Cu a été observée (P < 0,0001). Aucune différence n'a été observée entre les concentrations sériques chez les poulains cliniquement malades et cliniquement sains au premier jour de leur vie. Le statut FPT n'était pas associé à une réduction des concentrations sériques de Se, Cu ou Zn. Conclusion et pertinence clinique: Il n'est pas nécessaire de supplémenter tous les poulains en oligo-éléments avec FPT.(Traduit par Dr Serge Messier).

The immune response to malaria in utero.

Malaria causes tremendous early childhood morbidity and mortality, providing an urgent impetus for the development of a vaccine that is effective in neonates. However, the infant immune response to malaria may be influenced by events that occur well before birth. Placental malaria infection complicates one quarter of all pregnancies in Africa and frequently results in exposure of the fetus to malaria antigens in utero, while the immune system is still developing. Some data suggest that in utero exposure to malaria may induce immunologic tolerance that interferes with the development of protective immunity during childhood. More recently, however, a growing body of evidence suggests that fetal malaria exposure can prime highly functional malaria-specific T- and B-cells, which may contribute to postnatal protection from malaria. In utero exposure to malaria also impacts the activation and maturation of fetal antigen presenting cells and innate lymphocytes, which could have implications for global immunity in the infant. Here, we review recent advances in our understanding of how various components of the fetal immune system are altered by in utero exposure to malaria, discuss factors that may tilt the critical balance between tolerance and adaptive immunity, and consider the implications of these findings for malaria prevention strategies.

Influence of Timing of Maternal Pertussis Immunization on the Avidity of Transferred Antibodies in Term and Preterm Neonates.

The timing of maternal pertussis vaccination influences the titers of cord-blood anti-pertussis antibodies. Whether it affects their avidity is unknown. We demonstrate in 298 term and 72 preterm neonates that antibody avidity is independent of the timing of maternal vaccination, whether comparing second with third trimester or intervals before birth.

HIV-Associated Alterations of the Biophysical Features of Maternal Antibodies Correlate With Their Reduced Transfer Across the Placenta.

BACKGROUND: Human immunodeficiency virus (HIV) infection during pregnancy is associated with reduced transplacental transfer of maternal antibodies and increased risk of severe infections in children who are exposed and uninfected with HIV. The basis of this reduced transfer of maternal immunity has not yet been defined but could involve modifications in the biophysical features of antibodies. The objective of this study was to assess the impact of maternal HIV infection on the biophysical features of serum IgG and transplacental antibody transfer. METHODS: Maternal serum IgG subclass levels, Fc glycosylation, Fc receptor (FcR) binding, and transplacental transfer of pathogen-specific maternal IgG were measured in pregnant women with HIV (WWH) and pregnant women testing negative for HIV (WNH) in Cape Town, South Africa. RESULTS: Maternal antibody profiles were strikingly different between pregnant WWH and WNH. Antibody binding to FcγR2a and FcγR2b, IgG1 and IgG3 antibodies, and agalactosylated antibodies were all elevated in WWH, whereas digalactosylated and sialylated antibodies were reduced compared to pregnant WNH. Antibody features that were elevated in WWH were also correlated with reduced transplacental transfer of vaccine antigen-specific antibodies. CONCLUSIONS: HIV infection is associated with marked alterations of biophysical features of maternal IgG and reduced placental transfer, potentially impairing antimicrobial immunity.

Effectiveness of Maternal Vaccination with mRNA COVID-19 Vaccine During Pregnancy Against COVID-19-Associated Hospitalization in Infants Aged <6 Months - 17 States, July 2021-January 2022.

COVID-19 vaccination is recommended for persons who are pregnant, breastfeeding, trying to get pregnant now, or who might become pregnant in the future, to protect them from COVID-19.§ Infants are at risk for life-threatening complications from COVID-19, including acute respiratory failure (1). Evidence from other vaccine-preventable diseases suggests that maternal immunization can provide protection to infants, especially during the high-risk first 6 months of life, through passive transplacental antibody transfer (2). Recent studies of COVID-19 vaccination during pregnancy suggest the possibility of transplacental transfer of SARS-CoV-2-specific antibodies that might provide protection to infants (3-5); however, no epidemiologic evidence currently exists for the protective benefits of maternal immunization during pregnancy against COVID-19 in infants. The Overcoming COVID-19 network conducted a test-negative, case-control study at 20 pediatric hospitals in 17 states during July 1, 2021-January 17, 2022, to assess effectiveness of maternal completion of a 2-dose primary mRNA COVID-19 vaccination series during pregnancy against COVID-19 hospitalization in infants. Among 379 hospitalized infants aged <6 months (176 with COVID-19 [case-infants] and 203 without COVID-19 [control-infants]), the median age was 2 months, 21% had at least one underlying medical condition, and 22% of case- and control-infants were born premature (<37 weeks gestation). Effectiveness of maternal vaccination during pregnancy against COVID-19 hospitalization in infants aged <6 months was 61% (95% CI = 31%-78%). Completion of a 2-dose mRNA COVID-19 vaccination series during pregnancy might help prevent COVID-19 hospitalization among infants aged <6 months.

Maternal- and Fetal-Encoded Perforin-2 Limits Placental Infection by a Bloodborne Pathogen.

Placental immune responses are highly regulated to strike a balance between protection and tolerance. For relatively mild infections, protection encompasses both the mother and fetus; however, during worsening conditions, protection becomes exclusively reserved for the mother. Previously, we and others have shown that the host factor perforin-2 plays a central role in protecting mice and cells against infection. In this study, we analyzed perforin-2 activity in the mouse placenta to determine whether perforin-2 plays a similarly protective role. We show that perforin-2 is critical for inhibiting Listeria monocytogenes colonization of the placenta and fetus and that this protection is due to both maternal and fetal-encoded perforin-2. Perforin-2 mRNA is readily detectable in individual immune cells of the decidua, and these levels are further enhanced specifically in decidual macrophages during high-dose infections that result in fetal expulsion. Unexpectedly, inductive perforin-2 expression in decidual macrophages did not occur during milder infections in which fetal viability remained intact. This pattern of expression significantly differed from that observed in splenic macrophages in which inductive perforin-2 expression was observed in both high and mild infection conditions. In the placenta, inductive perforin-2 expression in decidual macrophages was coincident with their polarization from a CD206+ MHC class IIlo to CD206- MHC class IIhi phenotype that normally occurs in the placenta during high-burden infections. Our results suggest that perforin-2 is part of a host response that is protective either for both the mother and fetus in milder infections or exclusively for the mother during high-dose infections.