Development of vaccine approaches to elicit broadly protective influenza-specific immune responses in infants

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Principal Investigator: Martha Ann Alexander-Miller
Organization: WAKE FOREST UNIVERSITY HEALTH SCIENCES
Fiscal Year: 2024
Award: $721,045
Funding agency: National Institute of Allergy and Infectious Diseases

Influenza virus infection of neonates can lead to life-threatening disease. The rate of LRTI-associated
hospitalizations is >4 times higher in children less than 1 year of age compared to those between 1 and 4
years and infants younger than 6 months of age are particularly vulnerable to the development of severe
disease. Current influenza vaccines on the market are not approved for infants <6 months of age as a result of
their limited effectiveness in this age group. Overcoming this poor responsiveness will require development of
vaccines with greater immunogenicity in this population. Another important area of investigation is the ability of
infants to respond to universal vaccines designed to provide protection across multiple strains of influenza.
While targeting production of these antibodies by vaccination is highly desirable, our understanding of how
effectively newborns can produce them or the accessory signals that can optimally elicit these antibodies is
unknown. The ultimate goal of the studies proposed in this application is to identify a vaccine approach for
influenza that is safe and broadly protective when delivered to neonates. To evaluate potential strategies, we
will use our established African green monkey (AGM) nonhuman primate neonate model. Using this model we
previously found that conjugation of the TLR7/8 agonist R848 to inactivated influenza promotes significant
increases in virus-specific IgG and IFNγ-producing T cell responses, providing rationale for the continued
exploration of this adjuvant in neonates. We will utilize R848 together with heterologous boost or an HA stem
construct as approaches to elicit broadly reactive antibody. As part of our analyses we will evaluate the role of
Tfh responses in modulating broadly reactive antibody quantity and quality. The results of these studies will
provide mechanistic as well as practical information that may lead to the improved design of vaccines that will
be efficacious in the vulnerable neonate population.

Terms: <0-11 years old><0-4 weeks old><1 year of age><1 year old><21+ years old><7S Gamma Globulin><Ab response><Address><Adjuvant><Adult><Adult Human><Affinity><African Green Monkey><Age Months><Agonist><Animal Model><Animal Models and Related Studies><Antibodies><Antibody Formation><Antibody Production><Antibody Response><Antigens><Area><Assay><B blood cells><B cell><B cell differentiation><B cells><B lymphocyte differentiation><B-Cells><B-Lymphocytes><B-cell><Bioassay><Biological Assay><CD134><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Child><Child Youth><Children (0-21)><Chlorocebus aethiops><Chlorocebus sabaeus><Data><Development><Disease><Disorder><Dose><Effectiveness><Flu vaccination><Generations><Germinal Center><Goals><Green Monkey><Grippe><Hospital Admission><Hospitalization><Human><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><IgG><Immune><Immune Interferon><Immune response><Immune system><Immunes><Immunoglobulin G><Immunological response><Individual><Infant><Influenza><Influenza Vaccines><Influenza Virus><Influenza immunization><Influenza vaccination><Interferon Gamma><Interferon Type II><Intracellular Communication and Signaling><Investigation><Life><Ligands><Lower Respiratory Tract Infection><Lower respiratory infection><MF59><Maintenance><Marketing><Maternal antibody><Measures><Memory B Cell><Memory B-Lymphocyte><Mice><Mice Mammals><Modeling><Modern Man><Murine><Mus><NIAID><National Institute of Allergy and Infectious Disease><Newborn Infant><Newborns><OX40><Population><Position><Positioning Attribute><Predisposition><Prophylactic vaccination against influenza><Research><Risk><Role><Signal Transduction><Signal Transduction Systems><Signaling><Specificity><Structure of germinal center of lymph node><Susceptibility><T cell response><TLR7><TLR7 gene><Testing><Toll-Like Receptor 7><Vaccinated><Vaccination><Vaccine Design><Vaccines><Virus><Vulnerable Populations><Work><access to vaccination><access to vaccines><adaptive immune response><adulthood><age 1 year><age group><aged 1 year><aged one year><antibody biosynthesis><biological signal transduction><booster dose><booster shot><booster vaccine><develop a vaccine><develop vaccines><development of a vaccine><developmental><flu immunisation><flu infection><flu serotype><flu strain><flu subtype><flu vaccine><flu viral strain><flu virus infection><flu virus strain><flu virus vaccine><host response><immune system response><immunogen><immunogenicity><immunoglobulin biosynthesis><immunoresponse><improved><infancy><infant animal><infantile><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><influenza infection><influenza serotype><influenza strain><influenza subtype><influenza viral strain><influenza virus infection><influenza virus strain><influenza virus vaccination><influenza virus vaccine><influenzavirus><kids><lFN-Gamma><model of animal><nano particle><nano-sized particle><nanoparticle><nanosized particle><neonate><newborn child><newborn children><non-human primate><nonhuman primate><one year of age><one year old><pan influenza vaccine><pan influenza viral vaccine><pan influenza virus vaccine><pre-clinical><preclinical><response><social role><stem><universal flu vaccine><universal influenza vaccine><universal influenza virus vaccine><universal vaccine><universal vaccine against flu><universal vaccine against influenza><vaccination access><vaccination against influenza><vaccination availability><vaccine access><vaccine against flu><vaccine against influenza><vaccine availability><vaccine boost><vaccine candidate><vaccine development><vaccine response><vaccine responsiveness><vaccine safety><vaccine strategy><vaccine-induced response><vulnerable group><vulnerable individual><vulnerable people><youngster>