Rotavirus (RV) vaccine efficacy is significantly reduced in lower- and middle-income countries (LMICs) compared to high-income countries. This review summarizes current research into the mechanisms behind this phenomenon, with a particular focus on the evidence that maternal antibody (matAb) interference is a contributing factor to this disparity. All RV vaccines currently in use are orally administered, live-attenuated virus vaccines that replicate in the infant gut, which leaves their efficacy potentially impacted by both placentally transferred immunoglobulin G (IgG) and mucosal IgA Abs conferred via breast milk. Observational studies of cohorts in LMICs demonstrated an inverse correlation between matAb titers, both in serum and breast milk, and infant responses to RV vaccination. However, a causal link between maternal humoral immunity and reduced RV vaccine efficacy in infants has yet to be definitively established, partially due to limitations in current animal models of RV disease. The characteristics of Abs mediating interference and the mechanism(s) involved have yet to be determined, and these may differ from mechanisms of matAb interference for parenterally administered vaccines due to the contribution of mucosal immunity conferred via breast milk. Increased vaccine doses and later age of vaccine administration have been strategies applied to overcome matAb interference, but these approaches are difficult to safely implement in the setting of RV vaccination in LMICs. Ultimately, the development of relevant animal models of matAb interference is needed to determine what alternative approaches or vaccine designs can safely and effectively overcome matAb interference of infant RV vaccination.

Electronic cigarettes (e‐cigarettes) are nicotine delivery devices advertised as a healthier alternative to conventional tobacco products, but their rapid rise in popularity outpaces research on potential health consequences. As conventional tobacco use is a risk factor for osteoporosis, this study examines whether exposure to electronic liquid (e‐liquid) used in e‐cigarettes affects bone‐forming osteoblasts. Human MG‐63 and Saos‐2 osteoblast‐like cells were treated for 48 hours with 0.004%‐4.0% dilutions of commercially available e‐liquids of various flavors with or without nicotine. Changes in cell viability and key osteoblast markers, runt‐related transcription factor 2 and Col1a1, were assessed. With all e‐liquids tested, cell viability decreased in a dose‐dependent manner, which was least pronounced in flavorless e‐liquids, most pronounced in cinnamon‐flavored e‐liquids and occurred independently of nicotine. Col1a1, but not runt‐related transcription factor 2, mRNA expression was upregulated in response to coffee‐flavored and fruit‐flavored e‐liquids. Cells treated with a non‐cytotoxic concentration of fruit‐flavored Mango Blast e‐liquid with or without nicotine showed significantly increased collagen type I protein expression compared to culture medium only. We conclude that the degree of osteotoxicity is flavor‐dependent and occurs independently of nicotine and that flavored e‐liquids reveal collagen type I as a potential target in osteoblasts. This study elucidates potential consequences of e‐cigarette use in bone.

Human cytomegalovirus (HCMV) infection, the most common cause of congenital disease globally, affecting an estimated 1 million newborns annually, can result in lifelong sequelae in infants, such as sensorineural hearing loss and brain damage. HCMV infection also leads to a significant disease burden in immunocompromised individuals. Hence, an effective HCMV vaccine is urgently needed to prevent infection and HCMV-associated diseases. Unfortunately, despite more than five decades of vaccine development, no successful HCMV vaccine is available. This review summarizes what we have learned from acquired natural immunity, including innate and adaptive immunity; the successes and failures of HCMV vaccine human clinical trials; the progress in related animal models; and the analysis of protective immune responses during natural infection and vaccination settings. Finally, we propose novel vaccine strategies that will harness the knowledge of protective immunity and employ new technology and vaccine concepts to inform next-generation HCMV vaccine development. Expected final online publication date for the Annual Review of Virology, Volume 9 is September 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Congenital and perinatal infections are transmitted from mother to infant during pregnancy across the placenta or during delivery. These infections not only cause pregnancy complications and still birth, but also result in an array of pediatric morbidities caused by physical deformities, neurodevelopmental delays, and impaired vision, mobility and hearing. Due to the burden of these conditions, congenital and perinatal infections may result in lifelong disability and profoundly impact an individual's ability to live to their fullest capacity. While there are vaccines to prevent congenital and perinatal rubella, varicella, and hepatitis B infections, many more are currently in development at various stages of progress. The spectrum of our efforts to understand and address these infections includes observational studies of natural history of disease, epidemiological evaluation of risk factors, immunogen design, preclinical research of protective immunity in animal models, and evaluation of promising candidates in vaccine trials. In this review we summarize this progress in vaccine development research for Cytomegalovirus, Group B Streptococcus, Herpes simplex virus, Human Immunodeficiency Virus, Toxoplasma, Syphilis, and Zika virus congenital and perinatal infections. We then synthesize this evidence to examine how close we are to developing a vaccine for these infections, and highlight areas where research is still needed.

Approximately 1 in 200 infants is born with congenital cytomegalovirus (CMV), making it the most common congenital infection. About 1 in 5 congenitally-infected babies will suffer long-term sequelae, including sensorineural deafness, intellectual disability, and epilepsy. CMV infection is highly species-dependent, and the Rhesus CMV (RhCMV) infection of rhesus monkey fetuses is the only animal model that replicates essential features of congenital CMV infection in humans, including placental transmission, fetal disease, and fetal loss. To better understand the determinants and dynamics of congenital CMV transmission, we developed a mathematical model for placental transmission, comprising of maternal, placental, and fetal compartments using parameters from literature and experimental data from RhCMV seronegative rhesus macaques inoculated with RhCMV at 7.7-9.0 weeks of pregnancy. The model was then used to study the effect of the timing of inoculation, maternal immune suppression, and hyper-immune globulin infusion on the risk of placental transmission in the context of primary and reactivated chronic maternal CMV infection.

This study compared the ability of several human HIV envelope-directed monoclonal antibodies produced in plants with the same antibodies produced in mammalian cells for their ability to cross monkey and mouse placentas. We found that the two types of antibodies have comparable transfer efficiencies in mice, but they are differentially transferred across macaque placentas, consistent with a two-receptor IgG transport model in primates.

Breast milk secretory IgA antibodies provide a first line of defense against enteric infections. Despite this and an effective vaccine, human rotaviruses (RVs) remain the leading cause of severe infectious diarrhea in children in low- and middle-income countries (LMIC) where vaccine efficacy is lower than that of developed nations. Therapeutic strategies that deliver potently neutralizing antibodies into milk could provide protection against enteric pathogens such as RVs. We developed a murine model of maternal protective-transfer using systemic administration of a dimeric IgA (dIgA) monoclonal antibody. We confirmed that systemically-administered dIgA passively transferred into milk and stomach of suckling pups in a dose-dependent manner. We then demonstrated that systemic administration of an engineered potent RV-neutralizing dIgA (mAb41) in lactating dams protected suckling pups from RV-induced diarrhea. This maternal protective-transfer immunization platform could be an effective strategy to improve infant mortality against enteric infections, particularly in LMIC with high rates of breastfeeding.