Item Details

title

DESIGNING A BROADLY PROTECTIVE INFLUENZA VACCINE IN NEWBORN AFRICAN GREEN MONKEYS

author

Crofts, Kali Florence

abstract

After birth, newborns transition from a relatively sterile intrauterine environment to a world rich in microbes. Their immune system is uniquely positioned to tolerate this antigenic bombardment. Although necessary for the demands of early life, this altered immune landscape increases the risk of severe influenza virus infections and limits the ability to generate protective antibody (Ab) responses following seasonal vaccination. Thus, there is an urgent need to develop protective influenza vaccines for this age group. In addition to being poorly immunogenic in young infants, seasonal influenza vaccines provide limited protection against drifted or shifted IAV strains. To limit widespread mortality in the event of an IAV pandemic, the development of a universal IAV vaccine is essential. Further, understanding how a universal vaccine works in the context of the newborn immune system could extend protection to this age group. This dissertation evaluates the efficacy of the H1ssF vaccine—a hemagglutinin (HA) stem-bearing nanoparticle—in newborn African Green Monkeys (AGMs). Previous studies with this vaccine in adult animal models and clinical trials have demonstrated the potential to elicit broadly protective responses. Here, we tested the effectiveness of H1ssF in the presence of AddaVax, an MF59-like adjuvant in newborn AGMs. We demonstrated that newborns could generate robust stem-specific IgG responses that were cross-reactive across group 1 HA proteins after prime/boost vaccination. Interestingly, viral clearance in the lower respiratory tract varied but was associated with improved Ab quality, including both neutralizing activity and antibody-dependent cellular phagocytosis (ADCP). We also examined immune responses in the lung-draining lymph nodes following viral challenge, highlighting the potential for recalled stem-specific cellular immunity and expanded H5-specific Ab responses. To further enhance newborn immunity, we conjugated a TLR7/8 adjuvant (R848) directly to H1ssF and co-administered with AddaVax. This dual-adjuvanted approach improved the quantity and quality of stem-specific Abs as well as broadening Fc-mediated Ab functions following prime-boost vaccination. Viral loads were reduced in both the trachea and BAL following heterologous challenge. Overall, these studies highlight the potential of H1ssF as a protective vaccine for newborns, emphasizing the importance of appropriate adjuvant combinations to optimize humoral immunity during early life.

subject

Antibodies

B cells

Influenza

Newborns

Non Human Primates

Vaccines

contributor

Alexander-Miller, Martha A (advisor)

Lyles, Doug (committee member)

Ornelles, David (committee member)

Grayson, Jason (committee member)

Haas, Karen (committee member)

date

2025-03-12T08:36:48Z (accessioned)

2025 (issued)

degree

Microbiology & Immunology (discipline)

embargo

2027-03-11 (terms)

2027-03-11 (liftdate)

identifier

http://hdl.handle.net/10339/110323 (uri)

language

en (iso)

publisher

Wake Forest University

type

Dissertation