Vaccinations of Neonates through Breast-Milk Consumption
Research team
- Project leader: Heather Wilson
- Scientists: Volker Gerdts, Andy Potter
Overview
Mucosal surfaces are the primary site of entry for infectious agents during birth and the neonatal period. Vaccines have been highly successful in reducing illness and death caused by infectious disease but there are challenges associated with successful vaccination of the very young. As such, neonates often require multiple vaccinations before sustained and effective protection is achieved against many infectious diseases. In many communities, especially in the developing world, it is a challenge to repeat these vaccinations in a timely manner and the result is children who are susceptible to vaccine-preventable disease. Clearly, a new method of vaccination is required which can protect infants from disease without repeated intervention (i.e. booster vaccinations) by the medical community. Ideally, this new vaccination strategy should be cost-effective, and non- or minimally invasive without the need for booster vaccinations.
The conventional understanding of oral vaccination is that oral antigens induce tolerance, not immunity. However, in neonates, this convention may be contradicted. There is evidence that continual low dose exposure of neonates to antigens in maternal milk within the first few days of life can invoke immunity instead of tolerance. Reasons for this brief "window of immunogenicity" may be explained by the increased gut permeability in the neonate compared to adults and the fact that colonization of the neonatal gut with commensal bacteria is still being established.
Research Goal
The primary focus of this research project is the development of a novel vaccination strategy in which breast milk acts as the "route of administration" for a neonatal mucosal vaccine. We will administer a "vaccine" into the mother's mammaries which is in fact the genetic code for a strongly immunogenic antigen. The cells in the mammary gland which take up this genetic material will produce the antigen and secrete it into the breast milk. Upon consumption of the colostrum/milk, the neonatal immune system will recognize the antigen as foreign and mount its own immune response. We hypothesize that the neonate will be orally vaccinated against this antigen and any future challenge by bacteria expressing this antigen will elicit a secondary immune response.
In conjunction with developing an antigen-specific vaccine, we are also studying whether administration of the genetic codes for various host defense peptides to the mammaries glands (which will therefore be consumed by the neonate as maternally-derived peptides) protect against neonatal diarrheal diseases.
Objectives
- Establish whether orally derived antigens invoke immunity or tolerance.
- Develop Adeno-Associated Virus- pertussis toxoid (AAV-Ptd) vector or pGEX-Ptd (a DNA vectored vaccine).
- Establish that AAV-Ptd or pGEX-Ptd can infect or be taken up by mammary epithelial cells and express pertussis toxoid.
- Establish the most effective dose required to promote a productive and pertussis toxoid-specific immune response.
This vaccination strategy is novel for four reasons:
1. We are proposing to use mammary glands as a factory for secreting antigen/host defense peptides into breast milk. Our goal is not to generate maternal antibodies against the antigen and then passively transfer maternal antibodies to the neonate, it is to secrete antigen into breast milk which is then recognized by the neonatal immune system as foreign.
2. We intend to capitalize on the unique immunological and nutritional bond between mother and suckling infant to orally vaccinate the neonate.
3. Because the neonate will breast feed for many months, he/she will be continuously exposed to a low dose of antigen. This dose and time-frame of exposure is key to invoking oral immunity.
Continuous antigen exposure should result in long-term persistence of immune memory which should negate the need for multiple booster vaccinations. This strategy should therefore be extremely beneficial for mothers and suckling infants in the developing world where scheduling multiple vaccinations may be problematic.
Future Direction and Vision
We will expand into the study of other pediatric infectious disease models. Also, we will focus on needle-free vaccine administration to mammary tissues to reduce potential spread of communicable disease such as HIV. Eventually, we intend to prove efficacy and safety in human trials.
Funding Partners
