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The State University of New York, USA
Title: Recent progress in Human mucosal vaccine development: Role of Mucosal Immunity and Mucosal Microbiome in the outcome of vaccine effectiveness
Biography

Dr. Ogra’s career in medicine began in the early 1960’s. His academic leadership has focused on research, teaching and patient care in childhood infections, mucosal vaccine development, and definition of biologic markers of immunity against human infections. His major scientific contributions began with the first functional characterization of secretory IgA and “alimentary” mucosal immunity in natural or vaccine induced infection with poliovirus. In subsequent investigations, he defined the role of secretory IgA and cellular mucosal immune responses to such human infections as rubella, mumps, hepatitis B virus and enteroviruses. His laboratory provided extensive immunologic characterization of human milk, its role in maternal-neonatal interactions and childhood infections, and the association of mammary glands with other components of the common mucosal immune system. Other investigations from his laboratory identified important components of host-pathogen interactions underlying the pathogenesis of mucosal infections, notably in Bronchiolitis due to respiratory syncytial virus (RSV), gastroenteritis due to rotavirus, and immunologic aspects of Otitis media in childhood. These include, demonstration of RSV specific IgE in the respiratory mucosa and its role in viral induced reactive airway disease, identification of rotavirus- specific receptor-binding sites in villous enterocytes in early infancy and the role of Bifidobacteria in modulating rotavirus-mucosal cell interactions, and development of IgA and other aspects of mucosal immune responses in the middle ear mucosa during otitis media. Dr. Ogra served as the chief of Pediatric infectious diseases and Professor of Pediatrics and Microbiology at the University at Buffalo, State University of New York until 1990, when he was appointed as the John Sealy Distinguished Chair Professor and Chairman of the Department of Pediatrics at the University of Texas Medical Branch (UTMB), Pediatrician-in-Chief at the UTMB Children's Hospital, and as Professor of Microbiology and Immunology.. He retired from this position in 2002. Since that time, he has returned to the Children’s Hospital of Buffalo and is currently serving as Professor Emeritus, Department of Pediatrics at the State University of New York at Buffalo. Dr. Ogra has been a member of over 30 prestigious national and international scientific societies, These include election as ; Member, Association of American Physicians, American Society for Clinical Investigation, American Pediatric Society; Fellow ; Royal Society (Medicine) , London, UK . Infectious Diseases Society of America, American Academy of Microbiology. He has received multiple honors and awards, and has served as an honored guest and commencement speaker at medical school graduation events. He has served on many study sections, and national and international advisory panels of World Health Organization, National Institutes of Health (US) Institute of Medicine:, US National academy of Sciences, Federal Drug Administration ,International Vaccine Institute, Seoul, S. Korea, European Union ,Mucosal Vaccine Development Program (MUVAPRED). To date, Dr. Ogra has contributed over 440 peer reviewed original scientific publications and review articles. He has edited, in collaborations with many of his colleagues, 20 full-length books and monographs, has served as the founding editor of the first comprehensive textbook of Mucosal Immunology. During his investigative career, Dr. Ogra has served as the mentor of over 75 post-doctoral fellows and PhD students in Microbiology and Immunology and training of over 500 Pediatric residents. He continues to remain very active as a consultant and a teacher in the diverse areas of vaccine research and development and in the global issues of childhood infectious diseases. He devotes significant amount of his effort in the field in South Asia, towards the control of vaccine preventable diseases of the poor.

Abstract

One of the most successful and enduring accomplishments of mankind to date is the prevention or effective control of many infectious diseases through the use of vaccines. Most vaccines have been administered via the systemic (intramuscular/intracutaneous/subcutaneous) route. Such vaccines have resulted in significant decline in the disease burden of systemic infections associated with blood stream involvement, such as diphtheria, tetanus, pertussis, hemophilus influenzae, mumps, measles, rubella, and in the complete eradication of smallpox, Poliovirus type2 infection, and virtual elimination of other poliovirus types in most parts of the world. Systemic immunization has been highly effective in inducing systemic innate and adaptive immune responses, but limited or variable degree of immunity in the mucosal sites. Most human infections are acquired via the external mucosal surfaces of the respiratory, gastrointestinal, urogenital tracts. Human and other mammalian mucosal surfaces are in continuous contact with external environment and exposed to an overwhelming spectrum of microorganisms, dietary agents and other environmental macromolecules. It is estimated that the human intestinal mucosa alone contains >?10?^14 bacterial organisms representing as many as 2000 species , and over ?10?^11 virus -like particles/gm of feces, of nearly 1,000 viral species. In addition to the bacteria and viruses, human mucosal surfaces are the primary portals of entry and sites of initial colonization with many fungi and parasitic agents. However, pathogenic agents represent a very tiny fraction of the entire mucosal microbial repertoire .The mucosal surfaces of the human neonate begin to be colonized with components of maternal microbiome shortly before , during the process of birth and, subsequently within the first 2-3 weeks after birth from maternal and other environmental exposures. Studies over the past 5 decades have demonstrated an extensive and intercommunicative network of innate and adaptive immune mechanisms in the mucosa associated lymphoid tissue(MALT) distributed in the gut(GALT), upper Respiratory and bronchial epithelium (BALT), nose-nasopharynx-waldyers ring(NALT), Sublingual tissue(SLT),Urogenital tissue and mammary glands, and Skin(SALT). These lymphoid elements are collectively referred as the common mucosal Immune system. There is now increasing evidence to suggest that induction of protective immune response in the specific mucosal portals of entry is the most effective approach to regulate local colonization and subsequent disease outcome. Currently available mucosal vaccines include vaccines against, polioviruses,(live attenuated- oral)rotavirus(live attenuated –oral) influenza virus(live attenuated –nasal),vibrio cholera(inactivated-oral)and salmonella typhi (live attenuated-oral). Several other candidate mucosal vaccines are currently undergoing evaluations in human trials. These include, enterotoxigenic E.coli (ETEC), Shigella, Helicobacter, Campylobacter, Salmonella paratyphi, and Norovirus. The composition and the diversity of mucosal microbiome have been shown to have a profound influence on the induction of immune response and efficacy of mucosally introduced vaccines, especially in tropics. Other possible factors which influence the effectiveness of mucosal vaccines include, methods delivery of the infant (vaginal vs C-section) , postnatal feeding practices, malnutrition and carbohydrate consumption, use of antibiotics, and mucosal inflammation. Currently, mucosally delivered vaccines comprise of non- replicating whole organisms, synthetic peptides, inactivated toxins, and recombinant subunit proteins. In order to improve their immunogenicity and protective efficacy, the use of adjuvants has been explored in several clinical trials. These include, adjuvants which facilitate effective delivery of vaccine antigens ( liposomes, nanogels, oil-in-water emulsions); adjuvants directed at targeting vaccine antigens to professional antigen presenting cells (APC) (Virosomes). Finally, several adjuvants which stimulate the immune system itself are being explored currently in different settings. These include molecules binding to specific cellular receptors such as TLR, NOD and RIG1 like receptors, and DNA sensors.

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