Passive immunization to prevent vertical papillomavirus transmission in a preclinical mouse model

Human papillomaviruses (HPVs) are responsible for approximately 5% of all human cancers. Four vaccines have been approved for the prevention of cervical and oropharyngeal cancer. However, these vaccines offer no therapeutic benefit for preexisting infections. Infected mothers can transmit HPV to offspring through vertical transmission, either periconceptually, prenatally, perinatally, or neonatally. Recurrent respiratory papillomatosis (RRP), an aggressive and chronic disease in young children, is associated with the vertical transmission of low-risk HPV to infants. Currently, there is no cure, only invasive and repeated surgery. Novel interventions are highly desired for the prevention and treatment of RRP. Due in part to the species-specific and tissue-specific features of HPV, a mouse papillomavirus (MmuPV1) model that recapitulates some features of RRP has only recently been established. As one of the groups that have developed unique reagents and assays to monitoring MmuPV1 infections, we propose to test two novel hypotheses in the current proposal: 1) vertical PV transmission from infected mothers to babies is associated with the time of pregnancy and host immune status of the babies; 2) passive immunization with both polyclonal (pAb) and monoclonal (mAb) neutralizing antibodies can provide protection against oral infections in babies in a dose and time-dependent manner. Our hypotheses are built on both published and unpublished findings, including: 1) Passive immunization with anti- L1 sera can effectively block subsequent infections; 2) Among a panel of in-house mAbs raised against MmuPV1 L1, MPV.A4 can block MmuPV1 infection at both cutaneous and mucosal tissues; and 3) Vaginally infected mothers can transmit MmuPV1 to the oral cavity of offspring in Rag1ko mice. Two specific aims are proposed to test these hypotheses 1) Characterize vertical transmission by testing infected females and fetus at day 0, 7, 14 and 21 post vaginal plug formation after breeding naïve males for viral quantitation; 2) Determine the protection by passive immunization with mAb (MPV.A4) or pAb (anti-L1 sera) at day 0, 7, 14 post vaginal plug formation and monitoring oral infection in babies up to 24 weeks post-delivery. NU/J heterozygous (Foxn1nu/+) females which show detectable infections and advanced diseases at the genital tract after infection will be bred with naïve NU/J homozygous (Foxn1nu/nu) males. At the conclusion of the proposed study, we should have determined when vertical transmission occurs and whether host immune backgrounds are associated with susceptibility to vertical transmission. We will also have determined whether passive immunization with pAb and/or mAb can effectively block papillomavirus infection in babies and if it is time and dose dependent, as well as whether sex-associated protection exists, as we reported previously. An additional key opportunity with this model is that we can assess the effects of passive immunization on both clinical and subclinical PV diseases. Our study will be the first to compare both pAb and mAb against viral transmission in vivo and to determine whether sex and immune backgrounds play a role in passive immunization. Project Number: 1R21AI190337-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Jiafen Hu | Institution: PENNSYLVANIA STATE UNIV HERSHEY MED CTR, HERSHEY, PA | Award Amount: $234,900 | Activity Code: R21 | Study Section: Viral Dynamics and Transmission Study Section [VDT] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21AI19033701A1