The primary focus of the laboratory is to study immune protection against mother-to-child transmission (MTCT) of neonatal viral pathogens, such as HIV, cytomegalovirus (CMV), and Zika. We develop and utilize nonhuman primate models and human cohort studies to understand and elicit immune responses that can prevent vertical virus transmission, ultimately to determine the best vaccine approaches that target the naturally protective immune responses.
Immune protection against mother to child transmission (MTCT) of HIV-1
Nearly a quarter million infants continue to become infected with HIV-1 annually. Interestingly, in the absence of prophylactic interventions over half of infants are protected against virus acquisition. Thus, we are interested in defining the virus-specific immune responses that naturally protect infants against HIV-1 acquisition. We have studied this question by comparing the immune responses and virus variants present in HIV-infected transmitting and nontransmitting women, defining maternal and infant immune correlates of protection against MTCT. We have identified specific Envelope-specific antibody responses that are associated with protection against virus transmission in human cohorts. Moreover, using the nonhuman primate model of HIV/AIDS, simian immunodeficiency virus (SIV) or simian-human immunodeficiency virus (SHIV) infection of rhesus monkeys, we have defined the maternal and infant immune responses and virus characteristics that are associated with protection of the infant against virus acquisition and also can lead to viral cure. We have also studied the maternal immune responses and virus variant phenotypes natural primate hosts that evolved with SIV for tens of thousands of years, as they evolved mechanisms to largely protect their infants against SIV acquisition. Finally, we have utilized the nonhuman primate model as a platform for testing the effectiveness of maternal and infant HIV vaccination for protection of the infant against HIV-1 acquisition.
Mucosal immunity and vertical virus transmission
Breast milk provides important immunity against neonatal pathogens to the developing infant. Antibody, and primarily secretory IgA, is present in high concentration in breast milk. Therefore, we are interested in understanding the role of breast milk antibody in protecting the infant against viral pathogens such as HIV-1 and CMV. T and B lymphocytes are also present in breast milk, but their role in neonatal immunity is less clear. We have identified antiviral properties of these specialized breast milk lymphocyte populations and related their function to virus transmission. Moreover, we have identified an innate factors in breast milk, such as Tenascin-C, that neutralizes HIV-1 and may contribute to the inherently low rate of virus transmission via this route. We have devised ways to study these innate and adaptive immune responses in both humans and nonhuman primates. Moreover, we developed a model induced lactation in nonhuman primates so that this work does not rely on breeding cycles. Finally, we have utilized the nonhuman primate models to define ways in which we can target immune responses that will be passively transferred to the infant and could effectively block virus transmission. We hope to design strategies of maternal vaccination that will allow safe breastfeeding for all infants.
Maternal immune protection against perinatal cytomegalovirus transmission
Cytomegalovirus (CMV) complicates 1% of all pregnancies and results in 8,000 severe infections in U.S. children annually, resulting in brain damage, seizures, and vision and hearing loss. It is the leading nongenetic cause of infant hearing loss, accounting for 25% of all hearing loss, and causes more permanent disabilities in U.S. children then spina bifida or Down syndrome. Much like the rubella vaccine eliminated congenital rubella syndrome in this country, a vaccine that induces protection maternal immune responses in needed to protect against congenital CMV. Thus, our laboratory is working to identify the maternal immune responses that are required to protect against placental transmission of CMV in mother-infant cohort studies. Moreover, we have developed a nonhuman primate model of placental CMV transmission that can be employed to define the arms of the maternal immune response that is most necessary for protection of the fetus, as well as testing the efficacy of maternal CMV vaccines. We are also using this model to define the virologic determinants of placental virus transmission. Finally, as CMV can be pathogenic in very low birth weight preterm infants who acquire infection via breast milk feeding, we are also interested in harnessing the innate and adaptive maternal immune response to safely provide breast milk to this highly vulnerable population.
Maternal immune protection against ZIKV transmission
Thousands of babies have been born with congenital Zika syndrome as a result of the emergence of Zika virus (ZIKV) that has spread across the Americas and will continue to reach new ZIKV naive populations in the future. The ZIKV epidemic stands out as particularly alarming due to its association with poor pregnancy outcomes, including infant death and severe fetal neurologic damage manifesting as microcephaly, hearing and vision loss, and developmental delays. ZIKV has been linked to the startling rise in the cases of microcephaly among newborns in areas where it has become endemic. The epidemic and its alarming fetal consequences will result in a generation of disabled children in areas of the world that suffer from limited health care resources, leaving a considerable societal burden for decades to come.
A maternal vaccine is the only intervention that will protect all infants against ZIKV-associated permanent brain damage and birth defects. A passively administered protective ZIKV-neutralizing monoclonal antibody is a safe, ideal strategy to provide protection during the time window pre-conception and during pregnancy. Defining the quality and characteristics of the B cell repertoire to ZKV infection during acute and convalescent infection in pregnant women who naturally protected their infant against ZIKV disease will identify candidate neutralizing monoclonal antibodies that could be developed as prophylaxis agents.
Sallie Permar, MD, PhD, is a professor of pediatrics, immunology, and molecular genetics and microbiology at Duke University Medical Center. For more information and training opportunities, please visit the lab website: permarlabatduke.com.