Rochester General Hospital

NTHI IMMUNITY IN YOUNG CHILDREN

A PHASE II STUDY EVALUATING THE SAFETY AND EFFICACY OF WHOLE-CELL PNEUMOCOCCAL VACCINE (WSP) IN REDUCING NASOPHARYNGEAL COLONIZATION BY STREPTOCOCCUS PNEUMONIAE IN YOUNG CHILDREN - ABSTRACT. WHILE NEW, HIGHER-VALENCY PNEUMOCOCCAL CONJUGATE VACCINES( PCVS), PCV15 AND PCV20, WILL INCLUDE IMPORTANT SEROTYPES, THEIR IMPACT AND COST-EFFECTIVENESS WILL LIKELY BE LESS THAN WHAT WAS ACHIEVED WITH INTRODUCTION OF PCV7, PCV10 AND PCV13 BECAUSE, IN RECENT YEARS, PREVALENT SEROTYPES CAUSING INFECTIONS HAVE CHANGED AND CONTINUE TO CHANGE. HERE WE PROPOSE A CLINICAL STUDY, VACCINATING CHILDREN WITH A LOW COST-TO-PRODUCE, SEROTYPE-INDEPENDENT, KILLED, NON-CAPSULATED AVIRULENT WHOLE-CELL STREPTOCOCCUS PNEUMONIAE (WSP) VACCINE THAT ELICITS TH17 CELL-MEDIATED IMMUNITY AND ANTIBODIES AGAINST ALL PNEUMOCOCCAL SEROTYYPES, AND WHICH HAS BEEN TESTED IN ADULTS AND TODDLERS. NASOPHARYNGEAL (NP) COLONIZATION IS A PREREQUISITE TO PNEUMOCOCCAL DISEASES AND TRANSMISSION. WE WILL EVALUATE THE EFFICACY OF WSP VACCINATION IN YOUNG CHILDREN ON PNEUMOCOCCAL NP COLONIZATION AT TIMES OF HEALTH AND ONSET OF ACUTE OTITIS MEDIA. NOTABLY, PREVENTION OF PNEUMOCOCCAL NP COLONIZATION MAY BE A SURROGATE FOR PREVENTION BY WSP OF PNEUMOCOCCAL INFECTIONS. IN ADDITION, WE WILL CONFIRM THE SAFETY AND IMMUNOGENICITY OF WSP. DEMONSTRATION OF A REDUCTION OF NP COLONIZATION, SAFETY, IMMUNOGENICITY OF WSP WOULD ENGAGE THE SCIENTIFIC AND PUBLIC HEALTH COMMUNITY AND COMMERCIALIZATION SUPPORT FOR ADDITIONAL LICENSURE STUDIES TO NEXT TEST FOR PROTECTION AGAINST VARIOUS PNEUMOCOCCAL DISEASES, TO DETERMINE WHETHER WSP COULD COMPLEMENT PCVS OR EVEN REPLACE PCVS AS AN INEXPENSIVE, SEROTYPE-INDEPENDENT VACCINE.

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - CONSTRUCTION

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - NON-CONSTRUCTION - ROCHESTER GENERAL HOSPITAL COLLEGE OF HEALTH CAREERS WILL USE FUNDING FOR STUDENT SCHOLARSHIPS FOR LPN AND RN STUDENTS, AS WELL AS CREATE A SIMULATION LAB AND EXPANDED CLASSROOM SPACE FOR THESE VITAL NURSING TRAINING PROGRAMS.

HAEMOPHILUS INFLUENZAE LIPOPROTEIN FUSION VACCINE AND LIPOPROTEIN VACCINE PLATFORM DEVELOPMENT - ABSTRACT: A VACCINE TO PREVENT NONTYPEABLE HAEMOPHILUS INFLUENZAE (NTHI) INFECTIONS IS A MAJOR UNMET NEED. NTHI CAUSES RESPIRATORY INFECTIONS IN CHILDREN AND ADULTS INCLUDING ACUTE OTITIS MEDIA (AOM), ACUTE SINUSITIS, CONJUNCTIVITIS, ACUTE EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), NEUTROPHILIC ASTHMA AND INVASIVE DISEASE THAT LEADS TO HIGH MORBIDITY AND MORTALITY WORLDWIDE. PREVIOUSLY WE HAVE SHOWN LIPIDATION OF PROTEINS P6 AND OMP26 OF NTHI ENHANCES ANTIBODY AND TH17 IMMUNITY AND PROVIDES PROTECTION AGAINST NASOPHARYNGEAL (NP) COLONIZATION AND EAR INFECTION CAUSED BY NTHI COMPARED TO NON-LIPIDATED CONSTRUCTS. IN THIS PROJECT, WE WILL EVALUATE IMMUNOGENICITY AND PROTECTIVE EFFICACY OF NTHI LIPIDATED PROTEIN D AND PROTEIN F AND THEIR FUSION CONSTRUCTS VERSUS THEIR NON-LIPIDATED CONSTRUCTS AFTER SYSTEMIC VACCINATION IN A MOUSE MODEL OF NP COLONIZATION, EAR AND LUNG INFECTION. WE EXPECT OUR NOVEL LIPIDATED AND FUSION CONSTRUCTS TO ENHANCE SERUM AND MUCOSAL IGG ANTIBODY AND ACTIVATE TH17- MEDIATED IMMUNITY IN NASAL ASSOCIATED LYMPHOID TISSUE (NALT) ALONG WITH GENERATING T-CELL RESIDENT MEMORY (TRM) AGAINST NTHI. DIFFERENTIAL EFFECTS OF DIACYL VS TRIACYL VARIATION OF A LIPID MOIETY IN STIMULATION OF TLR2/TLR1 VS. TLR2/TLR6 WILL BE DETERMINED. WE HAVE SYNTHESIZED AND WILL TEST A QUADRIVALENT (L-OMP26ΦNL-P6ΦNL-PDΦNL-PF) FUSION (TRUNCATED VERSION OF EACH PROTEINS BASED ON THEIR FUNCTIONAL EPITOPES) MAKING ONLY ONE PROTEIN LIPIDATED ANTICIPATING ENHANCED IMMUNOGENICITY FOR ALL 4 PROTEINS. OVERALL THE PROJECT WILL EXPAND OUR UNDERSTANDING OF IMMUNE MECHANISMS ACTIVATED BY NOVEL LIPOPROTEIN NTHI FUSION VACCINE CONSTRUCTS AND IDENTIFY ANY DIFFERENCES IN IMMUNE RESPONSE ASSOCIATED WITH DIACYL VS. TRIACYL LIPIDATION (TLR2/TLR1 VS. TLR2/TLR6 ACTIVATION) ON PROTECTIVE EFFICACY AGAINST NTHI NP COLONIZATION, EAR AND LUNG INFECTION. THIS PROJECT WILL MORE BROADLY INNOVATE WITH A NOVEL LIPOPROTEIN VACCINE PLATFORM THAT MAY BE APPLIED TO OTHER PATHOGENS AND VACCINE CANDIDATE PROTEINS (INCLUDING THOSE THAT ARE NOT NATURALLY LIPIDATED) WHERE MUCOSAL COLONIZATION IS THE FIRST STEP OF PATHOGENESIS.

INSTITUTIONAL SUPPORT FOR COVID-19 RELIEF FOR THE ISABELLA GRAHAM HART SCHOOL OF PRACTICAL NURSING AT ROCHESTER GENERAL HOSPITAL.

THE NETWORK BIOLOGY OF PATHOGEN-HOST INTERACTIONS DRIVING EXACERBATION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)

SUPPORT FOR STUDENTS OF THE ISABELLA GRAHAM HART SCHOOL OF PRACTICAL NURSING.

ENHANCED IMMUNOGENICITY AND PROTECTION STUDY OF LIPID MODIFIED PROTEIN VACCINE CANDIDATES OF NONTYPEABLE HAEMOPHILUS INFLUENZAE

HEALTH CARE AND OTHER FACILITIES

AFFORDABLE CARE ACT (ACA) GRANTS FOR SCHOOL-BASED HEALTH CENTERS CAPITAL PROGRAM

AFFORDABLE CARE ACT (ACA) GRANTS FOR SCHOOL-BASED HEALTH CENTERS CAPITAL PROGRAM

ADDITIONAL SUPPORT FOR THE ISABELLA GRAHAM HART SCHOOL OF PRACTICAL NURSING DUE TO COVID-19.

ANALYSIS OF PRO-INFLAMMATORY MEMORY CD4 T-CELL SUBSETS TO INFLUENZA INFECTION

RECENTLY ARRIVED REFUGEES

HEALTH CARE AND OTHER FACILITIES

IMMUNE BIOMARKER DISCOVERY IN CHILDREN SUSCEPTIBLE TO RECURRENT OTITIS MEDIA - PROJECT SUMMARY/ABSTRACT VIRAL-BACTERIAL CO-INFECTIONS ARE OFTEN THE MOST SERIOUS INFECTIOUS EVENTS IN YOUNG CHILDREN, LEADING TO UNPLANNED OFFICE AND HOSPITAL VISITS AS WELL AS SIGNIFICANT MORBIDITY. ACUTE OTITIS MEDIA (AOM) IS A CANONICAL VIRAL-BACTERIAL CO-INFECTION, WHERE AN OPPORTUNISTIC NASOPHARYNGEAL COLONIZER ASCENDS THE EUSTACHIAN TUBE TO INFECT THE MIDDLE EAR DURING A CONCURRENT VIRAL UPPER RESPIRATORY INFECTION. IN A COHORT STUDY OF >1000 CHILDREN OVER THE LAST 14 YEARS, WE HAVE STUDIED AOM PATHOGENESIS, EPIDEMIOLOGY, AND IMMUNITY FROM SIX MONTHS TO FIVE YEARS OF AGE. CHILDREN PRONE TO MULTIPLE AOMS, TERMED STRINGENTLY-DEFINED OTITIS PRONE (SOP) CHILDREN IN OUR COHORT, COMPRISE APPROXIMATELY 10% OF THE TOTAL CHILD POPULATION BUT ACCOUNT FOR THE MAJORITY OF THE HEALTH CARE BURDEN DUE TO AOM AND ARE MORE LIKELY TO UNDERGO SURGERY FOR TYMPANOSTOMY TUBE INSERTION. IT IS CLEAR THAT SOP CHILDREN ARE COLONIZED EARLY IN LIFE WITH ONE OR MORE POTENTIAL OTOPATHOGENS COMPARED TO NON-OTITIS PRONE (NOP) CHILDREN, BUT THIS PREDICTIVE FEATURE OF SUSCEPTIBILITY REQUIRES CONTINUOUS MONITORING THROUGHOUT EARLY LIFE IN ORDER TO DETERMINE. PRELIMINARY DATA SUGGESTS THAT, IN ADDITION TO CHANGES IN NASOPHARYNGEAL (NP) OTOPATHOGEN COLONIZATION AND DEMOGRAPHIC RISK FACTORS, SOP CHILDREN HAVE A PRO-INFLAMMATORY PHENOTYPE IN THE NP AFTER ONE YEAR OF AGE. IMMUNE NETWORK MODELING OF THE NP IMMUNE RESPONSE TO AOM COMPARING SOP AND NOP CHILDREN SUGGESTS AN IL-6, IL-10, IL-17A, AND CCL5 IMMUNE NETWORK MAY BE RESPONSIBLE FOR THE IMMUNE DIFFERENCES OBSERVED IN SOP CHILDREN. FROM THESE DATA, OUR HYPOTHESIS IS THAT EARLY LIFE COLONIZATION WITH OTOPATHOGENS ALTERS NP IMMUNITY, THUS LEAVING SOME CHILDREN SUSCEPTIBLE TO RECURRENT AOM. FURTHER, SOLUBLE NP FACTORS CAN BE IDENTIFIED THAT, WHEN MEASURED IN EARLY LIFE, WILL BE A PREDICTOR OF RECURRENT AOM AND INFORM INDIVIDUALIZED CARE. AIM 1 WILL EMPLOY LC-MS BASED PROTEOMICS IN MATCHED SOP AND NOP SAMPLES TO DETERMINE THE NP PROTEOME AT DEFINED AGES BEFORE, DURING, AND AFTER AOM SUSCEPTIBILITY FOR BIOMARKER IDENTIFICATION. AIM 2 WILL MEASURE THE CANDIDATE BIOMARKERS FROM AIM 1 IN 400 NASAL WASH SAMPLES ACROSS THE CHILD COHORT TO DETERMINE ROBUSTNESS OF THE BIOMARKERS ACROSS CHILD AGE AND COVARIATES. THEREFORE, THIS GRANT PROPOSAL FOCUSES ON THE DETERMINATION OF A BIO-SIGNATURE PREDICTIVE OF SEVERE RECURRENT AOM AND THEREFORE THE NEED FOR TYMPANOSTOMY TUBE INSERTION VERSUS WATCHFUL WAITING THAT WILL BE MEASURED BEFORE OR DURING THE ONSET OF AOM INFECTIONS IN CHILDREN UNDER TWO YEARS OF AGE.

IMMUNOGENICITY OF MORAXELLA CATARRHALIS VACCINE CANDIDATES IN CHILDREN

ANTIBODY & CELLULAR IMMUNE RESPONSES IN CHILDREN AFTER 2 VS 3 DOSES AND PRE VS POST BOOSTER OF PCV13 VACCINE

IMMUNE POTENTIATION TO IMPROVE NEONATAL AND PEDIATRIC VACCINES

SCHOOL-BASED HEALTH CENTERS CAPITAL PROGRAM

BAKER-CEDERBERG ARCHIVAL COLLECTION PRESERVATION