Arnaud Marchant

Background: Infants who are HIV exposed but uninfected (iHEU) are more susceptible to severe infections in the first months of life when compared with infants who are HIV unexposed. Previous studies showed an association with reduced transplacental transfer of maternal antibodies. Whether maternal HIV infection also affects the persistence of transferred maternal antibodies is unknown. Methods: Serum samples were collected from 58 mother-infant pairs at delivery (maternal and cord blood) and at 1 month of age. A multiplex assay was established to test the levels of immunoglobulin G against tetanus, pertussis, cytomegalovirus, respiratory syncytial virus, and HIV. Results: When compared with infants who were HIV unexposed, iHEU had significantly lower antigen-specific antibody concentrations at 1 month across targeted pathogens, independent of maternal baselines and gestational ages. Impaired placental transfer and persistence of maternal antibodies contributed to the lower antibody levels in iHEU. Timing of antiretroviral therapy (ART) initiation in mothers had a profound impact on the dynamics of antibodies in iHEU. When compared with initiation of ART before pregnancy, iHEU whose mothers initiated ART during pregnancy had the lowest antibody concentrations at 1 month. Conclusions: Our study shows that in addition to reduced placental transfer, maternal HIV infection is associated with reduced persistence of maternal antibodies after birth. This reduction could contribute to the increased susceptibility of iHEU to severe infections and supports the need to offer vaccination during pregnancy to women with HIV. Our data provide encouragement for screening of HIV infection and initiation of ART before pregnancy to enhance immunity transferred to iHEU.

Solid-organ transplant (SOT) recipients are at enhanced risk of infection and to poorly respond to vaccination due to comorbidities and immunosuppression. We performed a systems vaccinology study in 59 kidney and 31 lung transplant recipients who received 3 doses of COVID-19 mRNA BNT162b2 vaccine. We were able to characterize a baseline configuration associated with an effective humoral response to 3 doses, characterized by an innate and activated B cell profile, whereas a T cell signature was associated with a poorer response. We observed a distinct configuration associated with a detectable humoral response to 2 doses, partly mediated by double negative B cell subsets. These results suggest that, despite their immunosuppression, some SOT recipients can induce an effective humoral response to 3 doses of vaccine supported by a baseline configuration close to the healthy phenotype. Baseline immune phenotyping may help identify SOT recipients at the greatest risk of a poor vaccine response.

BACKGROUND. Most humans have been infected with cytomegalovirus (CMV) by midlife without clinical signs of disease. However, in settings in which the immune system is undeveloped or compromised, the virus is not adequately controlled and consequently presents a major infectious cause of both congenital disease during pregnancy as well as opportunistic infection in children and adults. With clear evidence that risk to the fetus varies with gestational age at the time of primary maternal infection, further research on humoral responses to primary CMV infection during pregnancy is needed. METHODS. Here, systems serology tools were applied to characterize antibody responses to CMV infection in pregnant and nonpregnant women experiencing either primary or chronic infection. RESULTS. Whereas strikingly different antibody profiles were observed depending on infection status, limited differences were associated with pregnancy status. Beyond known differences in IgM responses used clinically for identification of primary infection, distinctions observed in IgA and FcγR-binding antibodies and among antigen specificities accurately predicted infection status. Machine learning was used to define the transition from primary to chronic states and predict time since infection with high accuracy. Humoral responses diverged over time in an antigen-specific manner, with IgG3 responses toward tegument decreasing over time as typical of viral infections, while those directed to pentamer and glycoprotein B were lower during acute and greatest during chronic infection. CONCLUSION. In sum, this work provides insights into the antibody response associated with CMV infection status in the context of pregnancy, revealing aspects of humoral immunity that have the potential to improve CMV diagnostics. FUNDING. CYMAF consortium and NIH NIAID.

Solid organ transplant (SOT) recipients are at enhanced risk of adverse outcomes following infectious challenges due to immunosuppressive treatment and additional comorbidities. Unfortunately, SOT recipients are also poor responders to the key medical intervention to preventing infection: vaccines. Here we performed a systems vaccinology study on a cohort of 59 kidney transplant recipients and 31 lung transplant recipients who received the mRNA Pfizer-BioNTech COVID-19 vaccine. Analyzing the immunological status of the patients prior to vaccination, we were able to identify multiple immunological associates of relatively improved vaccine responses following two or three doses of mRNA-based SARS-CoV-2 vaccine. These immunological associates predicted, with 95.0% and 93.3% accuracy, vaccine response after the second and third dose, respectively. Comparison of the immunological associates with vaccine response in SOT recipients revealed two distinct immune configurations: a non-classical configuration, distinct from the immune state of healthy subjects, associated with responses to two doses of mRNA vaccine and that could be mediated partly by the presence of double negative B cell subsets which are more prominently represented in responsive SOT recipients, and a “normalized” configuration, closer to the immune state of healthy subjects, associated with potent antibody responses to three doses of mRNA vaccine. These results suggest that immunosuppression in SOT recipients can result in distinct immune states associated with different trade-offs in vaccine responsiveness. Immune phenotyping of SOT recipients for immune constellation may be an effective approach for identifying patients most at risk of poor vaccine responses and susceptibility to vaccine-preventable diseases. One-sentence summary SOT recipients showed distinct immune states at baseline associated with different profiles of vaccine-associated immune response.