Innovations in Maternal, Neonatal, and Early Infancy Vaccines

Humans acquire a rich microbial ecosystem from their mothers at birth.  Myriad factors determine this microbiome acquisition and its evolution, including maternal health, antibiotics, delivery mode and infant diet. Patterns of infant microbiome colonization can alter the immune system, modify energy and nutrient bioconversion, and influence lifelong risk of nutrition-related metabolic diseases such as obesity and diabetes. As such, optimizing the maternal microbiome during pregnancy, seeding the newborn with favorable microbes at birth, and nourishing the infant, child and adult with a diet rich in microbiota-accessible foods holds promise for primordial disease prevention and health promotion. This talk will focus on the importance of mother-to-child transfer of microbiota, highlighting recent original research and putting forward a multi-pronged research agenda in this arena, including the potential role neonatal microbiota may play in vaccine efficacy.

Specific factors in breastmilk are known to protect against both diarrhoeal and respiratory tract infections. Factors such as the secretory IgA in milk, the human milk oligosaccharides and the milk microbiome are thought to play a role in protection against acquisition and clearance of pathogens such as Group B Streptococcus by direct action and by modulating the infant immune response. Whilst the study of breastmilk is in its infancy, its importance in protection against infection could provide unique opportunities for adjunctive therapies. Our understanding of the mechanisms by which breastmilk may reduce the risk of invasive disease in the neonatal period could allow us to harness the full potential of a maternal vaccine strategy, especially in countries where breastfeeding is the only viable infant feeding option.

Human cytomegalovirus (HCMV) is the most common congenitally transmitted pathogen worldwide, impacting an estimated 1 million newborns annually. Congenital HCMV infection is a major global contributor to long-term neurologic deficits, including deafness, microcephaly, and neurodevelopmental delay, as well as to fetal loss and infant mortality. Although pre-existing immunity reduces the risk of severe congenital disease, transmission frequently occurs in seropositive populations. How the intrauterine environment contributes to HCMV reactivation during pregnancy and the immune mechanisms that restrict viral dissemination are poorly understood. The robust induction of antiviral CD8+ and CD4+ T cells and potent neutralizing antibodies reactive with the viral pentamer complex gH/gL-pUL131-128 strongly correlate with protection from transmission. Moreover, HCMV infection induces tissue resident effector-memory T cells that restrict viral replication at sites of persistence and neutralizing antibodies that promote expansion of memory NK cells.  Whether these cells are present and confer protection within the decidua is under study. We have analyzed placentas from seropositive mothers with pregnancy complications and some with congenital Zika virus infection and found HCMV replicates in the epithelial cells of amniotic membranes and decidual glands suggesting that inflammation could impact local immune defenses and lead to transmission. This presentation describes early development of the human placenta, sites of viral replication in differentiating cytotrophoblasts, and local responses to infection by immune cells in the tissue environment during pregnancy.

The human cytomegalovirus is the most important cause of congenital infections and infectious complications of transplantation. Vaccines are being developed to prevent those.

Background The respiratory syncytial virus (RSV) fusion glycoprotein (F) facilitates virion and host cell membrane fusion during which it rearranges from a meta-stable prefusion to a stable postfusion conformation. Using structure-guided design, Pfizer engineered RSV prefusion F subunit vaccine antigen (RSVpreF) with stable, well-characterized conformational homogeneity.

Methods We report initial results of ~1182-subject, first-in-human, phase 1/2, placebo-controlled, randomized, observer-blind, dose-finding study to describe the safety, tolerability, and immunogenicity of RSVpreF in healthy men and non-pregnant women from 18 to 85 years of age. The study is ongoing to collect additional safety and immunogenicity data.

Results One-month-post-vaccination data for the 18- to 49-year-old subgroup demonstrate an excellent safety and tolerability profile. The vaccine elicited RSV 50% neutralizing titer geometric mean fold rises (GMFRs) of 10.6 to 17.2 for subgroup A and 10.4 to 19.8 for subgroup B with evidence of a dose-response. Responses trended higher in non-pregnant women compared to men. The ratio of RSV neutralizing titer GMFRs to RSV prefusion F binding IgG1 GMFRs (combining subgroup A and B data) ranged from 0.62 to 0.79 across vaccine dose levels.

Conclusions The 10- to 20-fold increases in neutralizing antibody titers and the high ratio of neutralizing to binding antibody titer GMFRs are a major advancement relative to the historical performance of F antigen vaccine candidates that were not stabilized in the prefusion conformation. The data strongly support development of this vaccine candidate to prevent RSV disease in infants, by immunizing pregnant women.

Group B streptococcus (GBS) sepsis is a leading cause of infant morbidity and mortality worldwide with approximately 90,000 infant deaths and 57,000 stillbirths occurring every year. It is the most important cause of meningitis in infants under 3 months of age. Vaccines administered during pregnancy have the potential to widely protect infants from early onset invasive GBS disease where universal intrapartum antibiotic prophylaxis (IAP) is not available, as well as to reduce late onset disease, meningitis, GBS-associated stillbirths and preterm births.Several maternal vaccines are in development to protect babies and their mothers against intrauterine GBS infection, with the most advanced candidate currently in phase 2 clinical development. Licensure trials may require large cohorts of pregnant women to demonstrate clinical vaccine efficacy.Alternatively, establishing an immunological correlate of protection in natural history studies using standardized assays may lead to accelerated vaccine approval followed by effectiveness studies. This presentation provides an overview of GBS vaccine development strategies towards licensure of GBS vaccines for use in lowand low-middle income countries.

Solving the structure of the RSV fusion glycoprotein (F) and distinguishing the conformations of prefusion and postfusion states led to the discovery of previously unrecognized NT-sensitive epitopes.Development of new candidate vaccines and monoclonal antibodies based on the understanding of the prefusion RSV F structure are now in advanced clinical development. Stabilized pre-F protein-based vaccines have been shown to be immunogenic in phase 1 adult trials and are now being tested in phase 2maternal immunization trials intended to passively protect infants with transplacental antibody. Another approach delivers neutralizing pre-F-specific monoclonal antibodies to neonates at birth to passively protect them through their first RSV season. Live-attenuated virus vaccines and gene-based delivery approaches are being developed for infants older than 6 months to protect during subsequent RSV seasons. Many of the advances in structure-based immunogen design and protein engineering pioneered in RSV vaccine development are now being successfully applied to other enveloped viruses that utilize class I fusion proteins including a variety of coronaviruses and paramyxoviruses.