Understanding and optimizing antibody-based interventions against neonatal HSV infection
Project Number5R01AI176646-02
Former Number1R01AI176646-01
Contact PI/Project LeaderACKERMAN, MARGARET E Other PIs
Awardee OrganizationDARTMOUTH COLLEGE
Description
Abstract Text
ABSTRACT
The fetal/neonatal period represents a unique period of vulnerability to viral infections. While
Herpesviruses such as herpes simplex virus (HSV) are highly prevalent and typically non life-threatening
infections among healthy adults, they are among the most consequential viral infections of early life. HSV
infection during parturition or the early postnatal period results in disseminated disease or encephalitis in up to
50% of infected newbowns. Without treatment, mortality is high and an estimated 70% of surviving infants with
central nervous system (CNS) involvement suffer long-term neurodevelopmental sequelae despite aggressive
treatment with acyclovir. Fortunately, newborns in our pathogen-rich world inherit some of the protection provided
by the maternal immune system in the form of transferred antibodies (Ab). For HSV, maternal Ab seropositivity,
resulting in placental transfer of Ab capable of directly neutralizing virus and eliciting the diverse effector functions
of the innate immune system, is associated with dramatically decreased risk of nHSV.
There is no currently approved HSV vaccine whereby maternal Abs could be induced among
seronegative mothers. As an alternative, our previous work has demonstrated that maternal Ab readily accesses
neural tissues of the fetus and is sufficient to prevent nHSV. Preliminary data now demonstrate a novel mouse
model system whereby we can model not only mortality and viral burden, but also behavioral pathologies that
are frequent and lifelong in humans following nHSV. The central hypothesis of this proposal is that the
development of effective vaccines and therapeutic antibodies for nHSV infections will benefit from careful in vivo
and in vitro evaluation of antibody mechanism(s) of action. Presently, there is a critical gap in knowledge of the
mechanisms whereby Ab-based interventions provide benefit in the context of nHSV infection, and how these
interventions might be optimized in order to best prevent this devastating disease.
Our objective is to define and refine the means by which monoclonal antibodies (mAbs) can be used
to prevent or reduce nHSV morbidity and mortality. We hypothesize that while Ab effector functions contribute
to direct neutralization activity, they are modulated by the viral Fc Receptor (vFcR), glycoprotein E (gE/gI
complex). Guided by strong preliminary data, the project goals will be achieved though completion of two
Specific Aims: 1) Define the mechanism(s) of action of mAbs that prevent nHSV, and 2) Define the role of the
viral Fc receptor (gE/gI) in influencing antiviral mAb activity.
Public Health Relevance Statement
NARRATIVE
Given the insufficiency of current interventions to reduce or prevent the lifelong morbidity and mortality
associated with neonatal herpes simplex virus (nHSV) infection, there is a critical need to develop new
therapies. A promising strategy is to use monoclonal antibodies to recapitulate the protection associated with
maternal antibodies whose placental transfer is capable of both virus neutralization and eliciting effector
functions of the innate immune system. The development of effective vaccines and therapeutic antibodies for
nHSV infections will benefit from a fuller understanding of antibody mechanism(s) of action that can prevent
this devastating disease.
National Institute of Allergy and Infectious Diseases
CFDA Code
855
DUNS Number
041027822
UEI
EB8ASJBCFER9
Project Start Date
14-August-2023
Project End Date
31-July-2028
Budget Start Date
01-August-2024
Budget End Date
31-July-2025
Project Funding Information for 2024
Total Funding
$785,011
Direct Costs
$526,443
Indirect Costs
$258,568
Year
Funding IC
FY Total Cost by IC
2024
National Institute of Allergy and Infectious Diseases
$785,011
Year
Funding IC
FY Total Cost by IC
Sub Projects
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