Vaccines are among the most impactful public health interventions, preventing millions of new infections and deaths annually worldwide. However, emerging data suggest that vaccines may not protect all populations equally. Specifically, studies analyzing variation in vaccine-induced immunity have pointed to the critical impact of genetics, the environment, nutrition, the microbiome, and sex in influencing vaccine responsiveness. The significant contribution of sex to modulating vaccine-induced immunity has gained attention over the last years. Specifically, females typically develop higher antibody responses and experience more adverse events following vaccination than males. This enhanced immune reactogenicity among females is thought to render females more resistant to infectious diseases, but conversely also contribute to higher incidence of autoimmunity among women. Dissection of mechanisms which underlie sex differences in vaccine-induced immunity has implicated hormonal, genetic, and microbiota differences across males and females. This review will highlight the importance of sex-dependent differences in vaccine-induced immunity and specifically will address the role of sex as a modulator of humoral immunity, key to long-term pathogen-specific protection.

Antibodies serve as the primary correlate of protection following most clinically approved vaccines and are thought to confer protection in part through their ability to block (neutralize) infection. Increasingly, studies have shown that beyond their blocking activities, the ability of antibodies to leverage the innate immune response may serve a vital role in protection from infection. Specifically, antibodies can drive phagocytosis, complement activation, and cellular cytotoxicity by interacting with Fc-receptors found on all innate immune cells. Measuring the capacity of antibodies to induce these functions has become critical for the identification of correlates of protection in large-scale vaccine trials. Therefore, there is a growing need to develop robust, high throughput assays able to interrogate the functional capacity of innate immune recruiting antibodies. However, in many instances, only small sample volumes are available. Nevertheless, profiling antibody functions across many pathogen-associated antigens or across global intra-pathogen variants is in high demand, making sample sparing approaches to perform this antibody evaluation critical. Here we describe the development of an approach to interrogate the functional activity of antibodies in serum against up to 5 antigen targets simultaneously. A single bead-based cellular assay was adapted to accommodate 5 different fluorescently colored beads, allowing for the concurrent investigation of antibody responses directed against multiple antigens in a single well. The multiplexed assay was as sensitive, specific, and accurate as the single antigen assay and robustly able to assess functional differences mediated by antibodies across different samples. These findings show multiplexing allows for accurate and more efficient analysis of antibody-mediated effector profiles.

Preterm newborns are more likely to suffer from infectious diseases at birth compared to children delivered at term. Whether this is due to compromised cellular, humoral, or organ-specific development remains unclear. To begin to define whether maternal–fetal antibody transfer profiles differ across preterm (PT) and fullterm (FT) infants, the overall quantity and functional quality of an array of 24 vaccine-, endemic pathogen-, and common antigen-specific antibodies were assessed across a cohort of 11 PT and 12 term-delivered maternal:infant pairs from birth through week 12. While total IgG levels to influenza, pneumo, measles, rubella, EBV, and RSV were higher in FT newborns, selective Fc-receptor binding antibodies was noted in PT newborns. In fact, near equivalent antibody-effector functions were observed across PT and FT infants, despite significant quantitative differences in transferred antibody levels. Moreover, temporal transfer analysis revealed the selective early transfer of FcRn, FcγR2, and FcγR3 binding antibodies, pointing to differential placental sieving mechanisms across gestation. These data point to selectivity in placental transfer at distinct gestational ages, to ensure that children are endowed with the most robust humoral immunity even if born preterm.

Background HIV-exposed, uninfected (HEU) children have a higher risk of severe infection than HIV-unexposed children, though the causes are poorly understood. Emerging data point to altered antibody transfer in women with HIV (WHIV), however, specific perturbations and the influence of ART and viremia remain unclear. Methods We evaluated antigen-specific transplacental antibody transfer across 14 antigens in paired maternal and umbilical cord plasma from 352 Ugandan women; 176 were WHIV taking ART. We measured antigen-specific IgG subclass (IgG1, 2, 3, 4) levels and antibody Fcγ receptor (FcγRn, 2a, 2b, 3a, 3b) binding profiles. We used Partial Least Squares Discriminant Analysis to define antigen-specific transplacental antibody transfer features. Results Global antibody transfer patterns were similar by maternal HIV serostatus, pointing to effective placental function in WHIV on ART. However, HEU umbilical cord antibody profiles were altered, driven by perturbed maternal seroprofiles. WHIV and paired HIV-exposed umbilical cord plasma had higher levels of chronic herpesvirus antibodies (P<0.01 for EBV, HSV) and lower levels of classic vaccine-induced antibodies (P<0.01 for tetanus, polio, HiB), suggesting that umbilical cord antibody profile differences arise from imbalanced WHIV immunity. Multivariate regression analysis demonstrated abnormal WHIV antibody profiles were associated with HIV viremia, lower CD4 count and post-conception ART initiation (P=0.01). Conclusions Preserved placental antibody transfer and perturbed immune-dominance profiles in WHIV shift the balance of immunity delivered to neonates, pointing to HIV-associated changes in maternal antibody profiles as a key determinant of compromised neonatal immunity. Maternal vaccination interventions may promote transfer of relevant, effective antibodies to protect HEU children against early-life infections.

Purpose of Review The design of an HIV vaccine remains an elusive but top priority. Data from the non-human primate model and the first moderately protective HIV vaccine trial (RV144) point to a role for qualitative changes in humoral immune functions in protection from infection. Here, we review the current understanding of the antibody response throughout HIV infection, the known correlates of protection, and current strategies to manipulate antibodies to put an end to the epidemic. Recent Findings Recent studies point to innate immune-recruiting antibody function in preventing infection as well as controlling viremia following infection. These data have begun to inform next-generation design of HIV vaccines and antibody therapies by uncovering new viral targets and antibody architectures to improve potency and breadth. Summary Emerging data illustrate a role for innate immune recruiting-antibodies in conferring protection against HIV infection as well as promoting viral control and clearance, offering an unprecedented opportunity to modulate and improve antibody function to fight HIV more effectively.