Current capsular polysaccharide-based Streptococcus pneumoniae vaccines are too expensive for their use in most of the world and result in protection to only a subset of circulating strains, which varies geographically. In addition, the incidence of disease caused by serotypes not covered in the vaccines is increasing as these strains fill the niche of the eliminated serotypes, a phenomenon referred to as serotype replacement. Thus, there is a need for the development of vaccines with broader, serotype-independent coverage. Protein-based vaccines that target conserved surface proteins have the potential to provide broad coverage at lower cost. Despite reports of the existence of over two hundred S. pneumoniae surface proteins, those that possess desirable characteristics for inclusion in a vaccine, namely eliciting a protective immune response, a high level of conservation among S. pneumoniae strains, and being essential for viability and/or virulence in order to limit immune escape, are much more limited in number. We hypothesize that functional redundancy is a major reason for the dispensability of many individual surface proteins. We recently used a genome-wide screen based on transposon-sequencing (Tn-seq) to identify a small set of essential surface proteins. In this project we will use Tn-seq for genetic interaction mapping to identify S. pneumoniae surface proteins that are functionally redundant. We will test a subset of singly essential and functionally redundant proteins as mono- and multivalent vaccines, respectively. This project will reveal a new set of protective S. pneumoniae antigens and will generate a new strategy of vaccine development against pathogens.

Public Health Relevance

The goal of this proposal is to test a new concept in identifying vaccine antigens against Streptococcus pneumoniae, which will limit immune escape. We will use a high-throughput genetic method to identify redundant pairs or sets of surface proteins with important roles in virulence, and then test these in multivalent vaccines. In parallel, we will generate and test monovalent vaccines by choosing singly essential surface proteins previously identified by us.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI110826-01A1
Application #
8891081
Study Section
Special Emphasis Panel (ZRG1-VMD-H (08))
Program Officer
Taylor, Christopher E,
Project Start
2015-01-01
Project End
2016-12-31
Budget Start
2015-01-01
Budget End
2015-12-31
Support Year
1
Fiscal Year
2015
Total Cost
$247,500
Indirect Cost
$97,500
Name
Tufts University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111