SARS-CoV-2 Antibodies in Commercial Immunoglobulin Products Show Markedly Reduced Cross-reactivities Against Omicron Variants.

PURPOSE: Patients with antibody deficiencies often receive maintenance treatment with donor plasma-derived immunoglobulin (Ig) preparations to decrease the incidence and severity of infections. We have previously shown that IgG antibodies to the original SARS-CoV-2 strain were not consistently present in off-the-shelf Ig batches produced up to approximately 18 months after the first identified case of COVID-19 in the USA and that Ig batches with anti-SARS-CoV-2 IgG primarily contained vaccine-induced spike specific antibodies. This study aimed to investigate the degree of cross-reactivity between vaccine-induced anti-SARS-CoV-2 antibodies against Wuhan strain and subsequent viral variants. METHODS: Samples were collected from 74 Ig batches supplied by three different commercial manufacturers. All batches were used at the Immunodeficiency Unit at the Karolinska University Hospital from the start of the SARS-CoV-2 pandemic until September 2022. Antibody quantity and potential to neutralize virus entry into host cells were assessed against the original SARS-CoV-2 Wuhan strain and the following nine variants: Alpha, Beta, Delta, IHU, and the Omicron BA.1, BA.1.1, BA.1 with spike mutation L452R, BA.2, and BA.3. RESULTS: Ig batches produced approximately 18 months after the SARS-CoV-2 outbreak (from around July 2021) and later consistently contained high quantities of antibodies that bind the Wuhan strain. The Ig batches had overall low reactivity to the SARS-CoV-2 nucleocapsid, which implies that plasma donor spike IgG essentially is the result of vaccination. We assessed the degree of cross-reactivity towards each virus variant by plotting the variant/Wuhan strain ratio, which was consistent regardless of production date, suggesting cross-reactivity with vaccine-induced antibodies rather than virus exposure in the plasma donor population. Viral variants that emerged later during the pandemic systematically had a lower reactivity ratio, except for the Delta and IHU variants. The Ig batches displayed markedly low neutralizing potential towards the Beta variant and all tested Omicron variants. CONCLUSION: Commercial Ig batches currently contain large quantities of SARS-CoV-2 vaccine-induced antibodies. Cross-reactivity with variant strains is evident but varies, with markedly low neutralizing potential observed against Omicron variants.

Increase in SARS-CoV-2 RBD-Specific IgA and IgG Antibodies in Human Milk From Lactating Women Following the COVID-19 Booster Vaccination.

BACKGROUND: The United States Centers for Disease Control and Prevention recommended a third dose or booster of the Pfizer-BioNTech Comirnaty (BNT162b2) COVID-19 mRNA vaccine in September 2021 for high-risk individuals. Pregnant and high-risk lactating women were encouraged to receive the booster to obtain potential prolonged protection for themselves and their infants. RESEARCH AIM: To investigate the ability of the booster vaccine to increase IgA and IgG antibodies specific to the receptor-binding domain of the SARS-CoV-2 spike protein in human milk compared to levels pre-booster. METHODS: This was a prospective one-group study with a pretest-posttest design. Six of 12 participants were recruited prospectively. Participants were instructed to collect ≥ 2 ounces of milk in the morning at 30 days and 1-day pre-booster, and 7, 14, 21, 30, 45, and 60 days post-booster. Levels of IgA and IgG antibodies specific to the receptor-binding domain of the SARS-CoV-2 spike protein were quantified in human milk via an ELISA assay. RESULTS: We found a significant increase in anti-receptor-binding domain-specific IgA and IgG antibodies in human milk 1-2 weeks after the Pfizer-BioNTech booster and at the study endpoint (45- and 60-days post-booster). CONCLUSIONS: This suggests that the booster vaccination enhances SARS-CoV-2 specific immunity in human milk, which may be protective for infants.

Longitudinal antibody response kinetics following SARS-CoV-2 messenger RNA vaccination in pregnant and nonpregnant persons.

BACKGROUND: For some vaccine-preventable diseases, the immunologic response to vaccination is altered by a pregnant state. The effect of pregnancy on SARS-CoV-2 vaccine response remains unclear. OBJECTIVE: We sought to characterize the peak and longitudinal anti-S immunoglobulin G, immunoglobulin M, and immunoglobulin A responses to messenger RNA-based SARS-CoV-2 vaccination in pregnant persons and compare them with those in nonpregnant, reproductive-aged persons. STUDY DESIGN: We conducted 2 parallel prospective cohort studies among pregnant and nonpregnant persons who received SARS-CoV-2 messenger RNA vaccinations. Blood was collected at the time of first and second vaccine doses, 2 weeks post second dosage, and with serial longitudinal follow-up up to 41.7 weeks post vaccination initiation. Anti-S immunoglobulin M, immunoglobulin G, and immunoglobulin A were analyzed by enzyme-linked immunosorbent assay. We excluded those with previous evidence of SARS-CoV-2 infection by history or presence of antinucleocapsid antibodies. In addition, for this study, we did not include individuals who received a third or booster vaccine dosage during the study period. We also excluded pregnant persons who were not fully vaccinated (14 days post receipt of the second vaccine dosage) by time of delivery and nonpregnant persons who became pregnant through the course of the study. We studied the effect of gestational age at vaccination on the anti-S response using Spearman correlation. We compared the peak anti-S antibody responses between pregnant and nonpregnant persons using a Mann-Whitney U test. We visualized and studied the longitudinal anti-S antibody response using locally weighted scatterplot smoothing, Mann-Whitney U test, and mixed analysis of variance test. RESULTS: Data from 53 pregnant and 21 nonpregnant persons were included in this analysis. The median (interquartile range) age of the pregnant and nonpregnant participants was 35.0 (33.3-37.8) years and 36.0 (33.0-41.0) years, respectively. Six (11.3%) participants initiated vaccination in the first trimester, 23 (43.3%) in the second trimester, and 24 (45.3%) in the third trimester, with a median gestational age at delivery of 39.6 (39.0-40.0) weeks. The median (interquartile range) follow-up time from vaccine initiation to the last blood sample collected was 25.9 (11.9) weeks and 28.9 (12.9) weeks in the pregnant and nonpregnant cohort, respectively. Among pregnant persons, anti-S immunoglobulin G, immunoglobulin A, and immunoglobulin M responses were not associated with gestational age at vaccine initiation (all P>.05). The anti-S immunoglobulin G response at 2 weeks post second dosage was not statistically different between pregnant and nonpregnant persons (P>.05). However, the anti-S immunoglobulin M and immunoglobulin A responses at 2 weeks post second dosage were significantly higher in nonpregnant persons (P<.001 for both). The anti-S immunoglobulin G and immunoglobulin M levels 6 to 8 months after vaccine initiation fell to comparable proportions of the peak 2 weeks post second dosage antibody levels between pregnant and nonpregnant persons (immunoglobulin G P=.77; immunoglobulin M P=.51). In contrast, immunoglobulin A levels 6 to 8 months after vaccine initiation fell to statistically significantly higher proportions of peak 2 weeks post second dosage antibody levels in pregnant compared with nonpregnant persons (P=.002). Maternal anti-S immunoglobulin G levels were strongly correlated with umbilical cord anti-S immunoglobulin G levels (R=0.8, P<.001). CONCLUSION: The anti-S immunoglobulin A, immunoglobulin M, and immunoglobulin G response to SARS-CoV-2 vaccination in pregnancy is independent of gestational age of vaccine initiation. Maintenance of the immunoglobulin G response is comparable between pregnant and nonpregnant persons. The differential peak response of immunoglobulin M and immunoglobulin A and the differential decline of anti-S immunoglobulin A between pregnant and nonpregnant persons requires further investigation.

Kinetics of maternally-derived anti- SARS-CoV-2 antibodies in infants in relation to the timing of antenatal vaccination.

BACKGROUND: SARS-CoV-2 infection during early infancy can result in severe disease. We evaluated the durability of maternally-derived anti-SARS-CoV-2 antibodies in infants and its relation to antenatal vaccination timing. METHODS: Sera were prospectively collected at birth and 3 months after delivery from mother-infant pairs following antenatal BNT162b2 vaccination. SARS-CoV-2 receptor binding domain (RBD)-specific IgG levels and neutralizing activity were evaluated. RESULTS: 56 mother-infant pairs were included: 15 (26.8%) were vaccinated in the 1st trimester, 16 (28.6%) in the 2nd trimester, and 25 (44.6%) in the 3rd trimester.At the time of delivery, all neonates were positive for anti-RBD-specific IgG with a median concentration of 4046 [IQR 2446-7896] AU/mL, with the highest concentration found after 3rd trimester vaccination (median 6763 [IQR 3857-12561] AU/mL). At 3 months after delivery, anti RBD-specific IgG levels in infants significantly waned with a median concentration of 545 [IQR 344-810] AU/mL (P < 0.001). The half-life of anti-RBD-specific IgG was 66 days among mothers and 30 days among infants. While at the time of delivery, all neonates had detectable neutralizing activity regardless of gestational age at vaccination, at 3-months of age, a higher proportion of infants born to mothers vaccinated in 3rd trimester had persistent neutralizing activity as compared to those born to mothers vaccinated in 2nd trimester. CONCLUSIONS: Maternal vaccination leads to efficient transplacental antibody transfer, with persistent anti-SARS-CoV-2 antibodies detected at 3 months of age in all infants. The observed effect of antenatal immunization timing on the kinetics of maternally-derived antibodies may have implications for SARS-CoV-2 vaccination strategies.

SARS-CoV-2 IgG "heritage" in newborn: A credit of maternal natural infection.

Description of transplacental passage of specific SARS-CoV-2 IgG from mothers who contracted natural infection to their newborns. Retrospective cohort analysis including pregnant women diagnosed with SARS-CoV-2 and their newborns both tested for SARS-CoV-2 specific IgG and IgM with antibody titration at delivery. Nasopharyngeal swab were taken from both mothers and neonates, and tested for SARS-CoV-2 using polymerase chain reaction (PCR). IgM and IgG were analyzed in maternal and neonatal serum of 143 mother-infant dyads. 86% of women with a positive SARS-CoV-2 PCR >14 days before delivery developed specific IgG and 84% of their infants showed transplacental passage of IgG. Pregnant women infected with SARS-CoV-2 achieve antibody seroconversion following the kinetics described in the general population, and transplacental transfer of IgG specific antibodies occurs. No conclusion can be drawn on passive immunity efficacy or duration.

The impact on colostrum oxidative stress, cytokines, and immune cells composition after SARS-CoV-2 infection during pregnancy.

Background: Limited data are available regarding the differences between immunological, biochemical, and cellular contents of human colostrum following maternal infection during pregnancy with coronavirus 2 disease (COVID-19). Objective: To investigate whether maternal COVID-19 infection may affect immunological, biochemical, and cellular contents of human colostrum. Methods: Using a case-control study design, we collected colostrum from 14 lactating women with a previous diagnosis of COVID-19 during pregnancy and 12 without a clear diagnosis during September 2020 to May 2021. Colostrum samples were analysed for some enzymes and non-enzymatic oxidative stress markers (SOD, CAT, GPx, MDA, GSH, GSSG, H2O2, MPO) and for IL-1ß, IL-6, tumour necrosis factor (TNF)-α, protein induced by interferon gamma (IP)-10, IL-8, IFN-λ1, IL12p70, IFN-α2, IFN-λ2/3, granulocyte macrophage colony stimulating factor (GM-CSF), IFN-ß, IL-10 and IFN-γ, along with IgA and IgG for the SARS-CoV-2 S protein. We perform immunophenotyping to assess the frequency of different cell types in the colostrum. Results: Colostrum from the COVID-19 symptomatic group in pregnancy contained reduced levels of H2O2, IFN-α2, and GM-CSF. This group had higher levels of GSH, and both NK cell subtypes CD3-CD56brightCD16-CD27+IFN-γ+ and CD3-CD56dimCD16+CD27- were also increased. Conclusion: The present results reinforce the protective role of colostrum even in the case of mild SARS-Cov-2 infection, in addition to demonstrating how adaptive the composition of colostrum is after infections. It also supports the recommendation to encourage lactating women to continue breastfeeding after COVID-19 illness.

Favorable Outcome Following Sotrovimab Monoclonal Antibody in a Patient with Prolonged SARS-CoV-2 Omicron Infection with HIV/AIDS.

Persistent viral shedding or prolonged coronavirus disease 2019 (COVID-19) symptom is one of unresolved problem in immunocompromised individuals. We herein report an HIV/AIDS patient with Pneumocystis jirovecii pneumonia and prolonged COVID-19, possibly due to immune reconstitution inflammatory syndrome. His viral shedding and COVID-19 symptoms persisted for 39 days but were promptly resolved following sotrovimab monoclonal antibody therapy. This case suggests that prolonged COVID-19 and persistent viral shedding due to severe cellular immunodeficiency can occur in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) omicron infection and that sotrovimab is effective in the treatment of prolonged COVID-19 caused by omicron/BA.1.

Convalescent Plasma for COVID-19: A Single Center Prospective Experience with Serial Antibody Measurements and Review of the Literature.

BACKGROUND: High-titer convalescent plasma given early for COVID-19 may decrease progression into a severe infection. Here, we reported a study of serial antibody measurements in patients who received CP at our center and performed a systematic review of randomized trials on CP. METHODS: Our center participated in the Mayo Clinic Expanded Access Program for COVID-19 Convalescent Plasma. Patients diagnosed with COVID-19 by nasopharyngeal polymerase chain reaction at our center between April and August 2020 were included in the study if staffing was available for specimen collection. Through a colloidal gold immunochromatography assay, these patients' IgM and IgG antibody responses were measured at baseline (Day 0) and after transfusion (Day 1, 2, etc.). Donor CP antibody levels were measured as well. RESULTS: 110 serum specimens were obtained from 21 COVID-19 patients, 16 of whom received CP. The median time from developing symptoms to receiving CP was 11 days (range 4-21). In 9 of 14 (64%) cases where both recipient and donor CP antibody levels were tested, donor COVID-19 IgG was lower than that of the recipient. Higher donor antibody levels compared with the recipient (R = 0.71, p < 0.01) and low patient IgG before CP transfusion (p = 0.0108) correlated with increasing patient IgG levels from baseline to Day 1. Among all patients, an increased COVID-19 IgG in the short-term and longitudinally was positively correlated with improved clinical outcomes (ρ = 0.69, p = 0.003 and ρ = 0.58, p < 0.006, respectively). CONCLUSIONS: In a real-world setting where donor CP was not screened for the presence of antibodies, CP in donors might have less COVID-19 IgG than in recipients. An increase in patient antibody levels in the short term and longitudinally was associated with improved clinical outcomes.

Antibodies in the breastmilk of COVID-19 recovered women.

OBJECTIVE: Human milk contains antibodies against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) which may serve as a protective factor through passive immunization in infants. The objective of this study was to measure the levels of anti-SARS-CoV-2 IgG and IgA in human milk and serum after a SARS-CoV-2 infection. DESIGN: Breast milk and serum samples from 72 lactating mothers with confirmed SARS-CoV-2 asymptomatic or symptomatic infection were collected 1-229 days after the onset of clinical symptoms related to COVID-19. Seventeen mothers with no history of COVID-19 served as a control group. Enzyme-Linked ImmunoSorbent Assay was performed to analyze antibodies against SARS-CoV-2. RESULTS: SARS-CoV-2-IgA human milk antibodies were detected in mothers and their concentrations were consistently higher than SARS-CoV-2-IgG antibodies. The serum and breastmilk samples of women with COVID-19 was characterized by a higher concentration of anti-RBD IgA and IgG than the serum from the control group without COVID-19. No statistically significant difference was observed between the antibody levels in the serum samples obtained from symptomatic and asymptomatic women exposed to SARS-CoV-2 and between the antibody level and the time from a positive SARS-CoV-2 test result over the period studied. CONCLUSION: Our results confirm the presence of SARS-CoV-2 IgA and IgG antibodies in the breastmilk of COVID-19 recovered women and the possibility of these antibodies in providing specific immunologic benefits to breastfeeding infants such as protection against the virus transmission and severity of the acquired COVID-19 disease.

Anti-SARS-CoV-2 antibodies in breast milk during lactation after infection or vaccination: A cohort study.

Breast milk is a pivotal source to provide passive immunity in newborns over the first few months of life. Very little is known about the antibody transfer levels over the period of breastfeeding. We conducted a prospective study in which we evaluated concentrations of anti-SARS-CoV-2 Spike IgA and RBD IgG/M/A antibodies in maternal serum and breast milk over a duration of up to 6 months after delivery. We compared antibody levels in women with confirmed COVID-19 infection during pregnancy (n = 16) to women with prenatal SARS-CoV-2 vaccination (n = 5). Among the recovered women, n = 7 (44%) had been vaccinated during the lactation period as well. We observed intraindividual moderate positive correlations between antibody levels in maternal serum and breast milk (r = 0.73, p-value<0.0001), whereupon the median levels were generally higher in serum. Anti-RBD IgA/M/G transfer into breast milk was significantly higher in women recovered from COVID-19 and vaccinated during lactation (35.15 AU/ml; IQR 21.96-66.89 AU/ml) compared to the nonvaccinated recovered group (1.26 AU/ml; IQR 0.49-3.81 AU/ml), as well as in the vaccinated only group (4.52 AU/ml; IQR 3.19-6.23 AU/ml). Notably, the antibody level in breast milk post SARS-CoV-2 infection sharply increased following a single dose of vaccine. Breast milk antibodies in all groups showed neutralization capacities against an early pandemic SARS-CoV-2 isolate (HH-1) and moreover, also against the Omicron variant, although with lower antibody titer. Our findings highlight the importance of booster vaccinations especially after SARS-CoV-2 infection in pregnancy in order to optimize protection in mother and newborn.

Evidence of Maternal Antibodies Elicited by COVID-19 Vaccination in Amniotic Fluid: Report of Two Cases in Italy.

With SARS-CoV-2 infection, pregnant women may be at a high risk of severe disease and adverse perinatal outcomes. A COVID-19 vaccination campaign represents the key strategy to combat the pandemic; however, public acceptance of maternal immunization has to be improved, which may be achieved by highlighting the promising mechanism of passive immunity as a strategy for protecting newborns against SARS-CoV-2 infection. We tested the anti-SARS-CoV-2 antibody response following COVID-19 full-dose vaccination in the serum and amniotic fluid of two pregnant women who presented between April and June 2021, at the Center for the Treatment and Prevention of Infections in Pregnancy of the National Institute for Infectious Diseases "L. Spallanzani", for antenatal consultancy. Anti-SARS-CoV-2 IgG was found in residual samples of amniotic fluid collected from both women at the 18th week of gestation (63 and 131 days after the second dose's administration). Titers in amniotic fluid mirrored the levels detected in serum and were inversely linked to the time from vaccination. Our results suggest that antibodies elicited by COVID-19 vaccination can cross the placenta and reach the fetus; therefore, they may offer passive immunity at birth. It is critical to fully understand the kinetics of the maternal response to vaccination, the efficiency of IgG transfer, and the persistence of antibodies in infants to optimize maternal immunization regimens.

Quantification and Progress Over Time of Specific Antibodies Against Severe Acute Respiratory Syndrome Coronavirus 2 in Breast Milk of Lactating Women Vaccinated With BNT162b2 Pfizer-BioNTech Coronavirus Disease 2019 Vaccine (LacCOVID).

Background: Several observational studies demonstrated the passage of postvaccine antibodies through breast milk in women vaccinated against coronavirus disease 2019 (COVID-19), mostly with messenger RNA (mRNA)-based vaccines, but lacked long-term data. Methods: A 6-month prospective cohort study was performed to determine severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine-induced antibody levels in the breast milk of 33 lactating healthcare workers at different timepoints after mRNA BNT162b2 Pfizer-BioNTech COVID-19 vaccination. Moreover, we examined the correlation of SARS-CoV-2 antibody levels between serum and breast milk, adverse events related to vaccination, and rate of SARS-CoV-2 infections. Results: Mothers' median age was 38 (interquartile range [IQR], 36-39) years and 15 (IQR, 10-22) months for infants. Median (IQR) SARS-CoV-2 immunoglobulin G (IgG) spike protein subunit S1 (S1) vaccine-induced levels at different timepoints for serum-milk pairs were 519 (234-937) to 1 (0-2.9) arbitrary units (AU)/mL at 2 weeks after first dose and 18 644 (9923-29 264) to 78 (33.7-128), 12 478 (6870-20 801) to 50.4 (24.3-104), 4094 (2413-8480) to 19.9 (10.8-51.9), 1350 (831-2298) to 8.9 (7.8-31.5) AU/mL at 2, 4, 12 and 24 weeks after second dose, respectively. We observed a positive correlation of antibody levels between serum and breast milk, no serious adverse events related to vaccination, and 2 (6%) COVID-19 vaccine breakthrough infections. Conclusions: Women vaccinated with Pfizer-BioNTech transmit antibodies into breast milk with a positive correlation with serum levels. Both decreased over time in a 6-month follow-up.

Neutralizing COVID-19 Convalescent Plasma in Adults Hospitalized With COVID-19: A Blinded, Randomized, Placebo-Controlled Trial.

BACKGROUND: Convalescent plasma has been one of the most common treatments for COVID-19, but most clinical trial data to date have not supported its efficacy. RESEARCH QUESTION: Is rigorously selected COVID-19 convalescent plasma with neutralizing anti-SARS-CoV-2 antibodies an efficacious treatment for adults hospitalized with COVID-19? STUDY DESIGN AND METHODS: This was a multicenter, blinded, placebo-controlled randomized clinical trial among adults hospitalized with SARS-CoV-2 infection and acute respiratory symptoms for < 14 days. Enrolled patients were randomly assigned to receive one unit of COVID-19 convalescent plasma (n = 487) or placebo (n = 473). The primary outcome was clinical status (disease severity) 14 days following study infusion measured with a seven-category ordinal scale ranging from discharged from the hospital with resumption of normal activities (lowest score) to death (highest score). The primary outcome was analyzed with a multivariable ordinal regression model, with an adjusted odds ratio (aOR) < 1.0 indicating more favorable outcomes with convalescent plasma than with placebo. In secondary analyses, trial participants were stratified according to the presence of endogenous anti-SARS-CoV-2 antibodies ("serostatus") at randomization. The trial included 13 secondary efficacy outcomes, including 28-day mortality. RESULTS: Among 974 randomized patients, 960 were included in the primary analysis. Clinical status on the ordinal outcome scale at 14 days did not differ between the convalescent plasma and placebo groups in the overall population (aOR, 1.04; one-seventh support interval [1/7 SI], 0.82-1.33), in patients without endogenous antibodies (aOR, 1.15; 1/7 SI, 0.74-1.80), or in patients with endogenous antibodies (aOR, 0.96; 1/7 SI, 0.72-1.30). None of the 13 secondary efficacy outcomes were different between groups. At 28 days, 89 of 482 (18.5%) patients in the convalescent plasma group and 80 of 465 (17.2%) patients in the placebo group had died (aOR, 1.04; 1/7 SI, 0.69-1.58). INTERPRETATION: Among adults hospitalized with COVID-19, including those seronegative for anti-SARS-CoV-2 antibodies, treatment with convalescent plasma did not improve clinical outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04362176; URL: www. CLINICALTRIALS: gov.

Autoantibodies and autoimmune disorders in SARS-CoV-2 infection: pathogenicity and immune regulation.

Coronavirus disease 2019 (COVID-19) is an infectious disease associated with the respiratory system caused by the SARS-CoV-2 virus. The aim of this review article is to establish an understanding about the relationship between autoimmune conditions and COVID-19 infections. Although majority of the population have been protected with vaccines against this virus, there is yet a successful curative medication for this disease. The use of autoimmune medications has been widely considered to control the infection, thus postulating possible relationships between COVID-19 and autoimmune diseases. Several studies have suggested the correlation between autoantibodies detected in patients and the severity of the COVID-19 disease. Studies have indicated that the SARS-CoV-2 virus can disrupt the self-tolerance mechanism of the immune system, thus triggering autoimmune conditions. This review discusses the current scenario and future prospects of promising therapeutic strategies that may be employed to regulate such autoimmune conditions.

Regulatory considerations for study of infant protection through maternal immunization.

Childhood Immunization is one of the critical strategies to decrease infant morbidity and mortality due to infectious diseases, but primary immunization schedules for infants in most countries start at 2 months of age. Childhood vaccines therefore begin providing adequate protection later in life, leaving infants vulnerable to infectious diseases and creating an immunity gap that results in higher morbidity and mortality among younger infants. Maternal immunization, the practice of vaccinating individuals during pregnancy, reduces the risk of infant infection primarily through the transfer of protective maternal antibodies to the fetus during late pregnancy. Although much progress has been made in public health policies to support maternal immunization research, inclusion of pregnant individuals and children in clinical trials remains challenging. This has resulted in paucity of evidence regarding safety and effectiveness of vaccines to support licensure of products intended for use during pregnancy and lactation to prevent disease in the infant. In addition, although safeguards for clinical research in pregnancy are supportive, experimental vaccines, e.g., Respiratory Syncytial Virus, are more complicated to study because data on safety, efficacy, and dosing are limited. This requires randomized controlled trials with safety monitoring for the mother, the fetus, and the infant with follow-up for at least 1 year or longer to assess long-term health outcomes that may be associated with peripartum vaccine exposure. The goal of this paper is to discuss the general regulatory considerations for clinical research to evaluate safety and effectiveness of vaccines administered during pregnancy to protect infants from disease. This could be useful to inform future vaccine trials. This discussion is not intended to provide agency guidance nor to articulate agency policy.

Neutralizing SARS-CoV-2 Antibodies in Commercial Immunoglobulin Products Give Patients with X-Linked Agammaglobulinemia Limited Passive Immunity to the Omicron Variant.

Immunodeficient individuals often rely on donor-derived immunoglobulin (Ig) replacement therapy (IGRT) to prevent infections. The passive immunity obtained by IGRT is limited and reflects the state of immunity in the plasma donor population at the time of donation. The objective of the current study was to describe how the potential of passive immunity to SARS-CoV-2 in commercial off-the-shelf Ig products used for IGRT has evolved during the pandemic. Samples were collected from all consecutive Ig batches (n = 60) from three Ig producers used at the Immunodeficiency Unit at Karolinska University Hospital from the start of the SARS-CoV-2 pandemic until January 2022. SARS-CoV-2 antibody concentrations and neutralizing capacity were assessed in all samples. In vivo relevance was assessed by sampling patients with XLA (n = 4), lacking endogenous immunoglobulin synthesis and on continuous Ig substitution, for plasma SARS-CoV-2 antibody concentration. SARS-CoV-2 antibody concentrations in commercial Ig products increased over time but remained inconsistently present. Moreover, Ig batches with high neutralizing capacity towards the Wuhan-strain of SARS-CoV-2 had 32-fold lower activity against the Omicron variant. Despite increasing SARS-CoV-2 antibody concentrations in commercial Ig products, four XLA patients on IGRT had relatively low plasma concentrations of SARS-CoV-2 antibodies with no potential to neutralize the Omicron variant in vitro. In line with this observation, three out the four XLA patients had symptomatic COVID-19 during the Omicron wave. In conclusion, 2 years into the pandemic the amounts of antibodies to SARS-CoV-2 vary considerably among commercial Ig batches obtained from three commercial producers. Importantly, in batches with high concentrations of antibodies directed against the original virus strain, protective passive immunity to the Omicron variant appears to be insufficient.

Milk From Women Diagnosed With COVID-19 Does Not Contain SARS-CoV-2 RNA but Has Persistent Levels of SARS-CoV-2-Specific IgA Antibodies.

Background: Limited data are available regarding the balance of risks and benefits from human milk and/or breastfeeding during and following maternal infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Objective: To investigate whether SARS-CoV-2 can be detected in milk and on the breast after maternal coronavirus disease 2019 (COVID-19) diagnosis; and characterize concentrations of milk immunoglobulin (Ig) A specific to the SARS-CoV-2 spike glycoprotein receptor binding domain (RBD) during the 2 months after onset of symptoms or positive diagnostic test. Methods: Using a longitudinal study design, we collected milk and breast skin swabs one to seven times from 64 lactating women with COVID-19 over a 2-month period, beginning as early as the week of diagnosis. Milk and breast swabs were analyzed for SARS-CoV-2 RNA, and milk was tested for anti-RBD IgA. Results: SARS-CoV-2 was not detected in any milk sample or on 71% of breast swabs. Twenty-seven out of 29 (93%) breast swabs collected after breast washing tested negative for SARS-CoV-2. Detection of SARS-CoV-2 on the breast was associated with maternal coughing and other household COVID-19. Most (75%; 95% CI, 70-79%; n=316) milk samples contained anti-RBD IgA, and concentrations increased (P=.02) during the first two weeks following onset of COVID-19 symptoms or positive test. Milk-borne anti-RBD IgA persisted for at least two months in 77% of women. Conclusion: Milk produced by women with COVID-19 does not contain SARS-CoV-2 and is likely a lasting source of passive immunity via anti-RBD IgA. These results support recommendations encouraging lactating women to continue breastfeeding during and after COVID-19 illness.

Comprehensive serologic profile and specificity of maternal and neonatal cord blood SARS-CoV-2 antibodies.

BACKGROUND: Initial studies on COVID-19 in pregnancy have demonstrated a range of neutralizing activity, but little has been published on the full profile of SARS CoV-2 related antibodies in maternal and cordblood. OBJECTIVE: This study aimed to describe the profile and specificity of maternal and neonatal cord blood antibody profiles in response to SARS-CoV-2 virus exposure. STUDY DESIGN: This was a prospective cohort study of delivering patients at Thomas Jefferson University Hospital from April 2020 to February 2021. The primary objective was to describe unique maternal and fetal antibody epitope titers and specificity in patients with COVID-19 history. Serologic profile was assessed with a multiplex platform. Antigens used were hemagglutinin trimer influenza A (Hong Kong H3); spike trimers for SARS-CoV-2, SARS-CoV-1, Middle East respiratory syndrome coronavirus, and betacoronaviruses HKU-1 and OC43; and spike N-terminal domain, spike receptor-binding domain, and nucleocapsid protein (full length) for SARS-CoV-2. RESULTS: Here, 112 maternal samples and 101 maternal and cord blood pairs were analyzed. Of note, 37 patients had a known history of COVID-19 (positive polymerase chain reaction test) during pregnancy. Of 36 patients, 16 (44%) were diagnosed with COVID-19 within 7 days of delivery. Moreover, 15 of the remaining 76 patients (20%) without a known diagnosis had positive maternal serology. For those with a history of COVID-19, we identified robust immunoglobulin G response in maternal blood to CoV-2 nucleocapsid, spike (full length), and spike (receptor-binding domain) antigens with more modest responses to the spike (N-terminal domain) antigen. In contrast, the maternal blood immunoglobulin M response seemed more specific to spike (full length) epitopes than nucleocapsid, spike (receptor-binding domain), or spike (N-terminal domain) epitopes. There were significantly higher maternal and cord blood immunoglobulin G responses not only to CoV-2 spike (127.1-fold; standard deviation, 2.0; P<.00001) but also to CoV-1 spike (21.1-fold higher; standard deviation, 1.8; P<.00001) and Middle East respiratory syndrome spike (6.9-fold higher; standard deviation, 2.5; P<.00001). In contrast, maternal immunoglobulin M responses were more specific to CoV-2 spike (15.8-fold; standard deviation, 2.1; P<.00001) but less specific to CoV-1 (2.5-fold higher; standard deviation, 0.71; P<.00001) and no significant difference for Middle East respiratory syndrome. Maternal and cord blood immunoglobulin G antibodies were highly correlated for both spike and nucleocapsid (R2=0.96 and 0.94, respectively). CONCLUSION: Placental transfer was efficient, with robust nucleocapsid and spike responses. Both nucleocapsid and spike antibody responses should be studied for a better understanding of COVID-19 immunity. Immunoglobulin G antibodies were cross-reactive with related CoV-1 and Middle East respiratory syndrome spike epitopes, whereas immunoglobulin M antibodies, which cannot cross the placenta to provide neonatal passive immunity, were more SARS-CoV-2 specific. Neonatal cord blood may have significantly different fine specificity than maternal blood, despite the high efficiency of immunoglobulin G transfer.

Human Milk Antibodies after BNT162b2 Vaccination Exhibit Reduced Binding against SARS-CoV-2 Variants of Concern.

SARS-CoV-2-specific antibody responses are engendered in human milk after BNT162b2 vaccination. However, the emergence of variants of concern (VOCs) raises concerns about the specificity of and potential cross-protection mediated by milk antibody responses, which are crucial for passive immunity transferred from breastfeeding mothers to their infants. In this study, we collected milk samples at three different time points pre- and post-vaccination, and measured milk IgA antibody binding to the receptor binding domain (RBD) of the original Wuhan-Hu-1 strain, and the four VOCs, namely Alpha, Beta, Gamma and Delta. We report a significant level of anti-RBD IgA in milk collected at 4-6 weeks after the second dose of vaccination compared to pre-vaccination. We observed around a 30% reduction in binding to most VOCs, including the major circulating Delta variant, compared to the original Wuhan-Hu-1 strain. As COVID-19 vaccines may take some time to be approved for infants, these individuals remain at risk for severe disease and rely mainly on transferred passive immunity. Our findings support the current recommendations for vaccinating lactating women with the aim of transferring mucosal immunity to breastfeeding infants.

COVID-19 and Solid Organ Transplantation: Role of Anti-SARS-CoV-2 Monoclonal Antibodies.

Purpose of Review: Solid organ transplant recipients (SOTRs) are ideal candidates for early treatment or prevention of coronavirus disease 2019 (COVID-19) using anti-SARS-CoV-2 monoclonal antibodies because of multiple underlying medical conditions, chronic immune-suppression, sub-optimal immunogenic response to vaccination, and evolving epidemiological risks. In this article, we review pertinent challenges regarding the management of COVID-19 in SOTRs, describe the role of active and passive immunity in the treatment and prevention of COVID-19, and review real-world data regarding the use of anti-SARS-CoV-2 monoclonal antibodies in SOTRs. Recent Findings: The use of an anti-SARS-CoV-2 monoclonal antibody in high-risk solid organ transplant recipients is associated with a reduction in the risk of hospitalization, need for intensive care, and death related to COVID-19. Overall, the early experiences from a diverse population of solid organ transplant recipients who were treated with anti-spike monoclonal antibodies are encouraging with no reported acute graft injury, severe adverse events, or deaths related to COVID-19. Summary: Anti-SARS-CoV-2 antibodies are currently authorized for treatment of mild-moderate COVID-19 and post-exposure prophylaxis, including in SOTRs. Potential future uses include pre-exposure prophylaxis in certain high-risk persons and synergistic use along with emerging oral treatment options. Successful timely administration of anti-SARS-CoV-2 monoclonal antibodies requires a multidisciplinary team approach, effective communication between patients and providers, awareness of circulating viral variants, acknowledgement of various biases affecting treatment, and close monitoring for efficacy and tolerability.