TY - JOUR
T1 - The Group A Streptococcal Vaccine Candidate VAX-A1 Protects against Group B Streptococcus Infection via Cross-Reactive IgG Targeting Virulence Factor C5a Peptidase
AU - McCabe, Sinead
AU - Bjånes, Elisabet
AU - Hendriks, Astrid
AU - Wang, Zhen
AU - van Sorge, Nina M
AU - Pill-Pepe, Lucy
AU - Bautista, Leslie
AU - Chu, Ellen
AU - Codée, Jeroen D. C.
AU - Fairman, Jeff
AU - Kapoor, Neeraj
AU - Uchiyama, Satoshi
AU - Nizet, Victor
N1 - Funding Information: This work was supported by the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator (CARB-X, to Vaxcyte, Inc. and V.N.), the LeDucq Foundation for Cardiovascular Research (V.N.), and NIH/NIAID Grant (AI173689 to V.N.). E.B. was supported in part by an A.P. Giannini Postdoctoral Fellowship. The funders had no role in study design, data collection and interpretation, writing of the manuscript, or the decision to submit the manuscript for publication. Publisher Copyright: © 2023 by the authors.
PY - 2023/12/1
Y1 - 2023/12/1
N2 - Group B Streptococcus (Streptococcus agalactiae or GBS) is the leading infectious cause of neonatal mortality, causing roughly 150,000 infant deaths and stillbirths annually across the globe. Approximately 20% of pregnant women are asymptomatically colonized by GBS, which is a major risk factor for severe fetal and neonatal infections as well as preterm birth, low birth weight, and neurodevelopmental abnormalities. Current clinical interventions for GBS infection are limited to antibiotics, and no vaccine is available. We previously described VAX-A1 as a highly effective conjugate vaccine against group A Streptococcus that is formulated with three antigens, SpyAD, streptolysin O, and C5a peptidase (ScpA). ScpA is a surface-expressed, well-characterized GAS virulence factor that shares nearly identical sequences with the lesser studied GBS homolog ScpB. Here, we show that GBS C5a peptidase ScpB cleaves human complement factor C5a and contributes to disease severity in the murine models of pneumonia and sepsis. Furthermore, antibodies elicited by GAS C5a peptidase bind to GBS in an ScpB-dependent manner, and VAX-A1 immunization protects mice against lethal GBS heterologous challenge. These findings support the contribution of ScpB to GBS virulence and underscore the importance of choosing vaccine antigens; a universal GAS vaccine such as VAX-A1 whose formulation includes GAS C5a peptidase may have additional benefits through some measure of cross-protection against GBS infections.
AB - Group B Streptococcus (Streptococcus agalactiae or GBS) is the leading infectious cause of neonatal mortality, causing roughly 150,000 infant deaths and stillbirths annually across the globe. Approximately 20% of pregnant women are asymptomatically colonized by GBS, which is a major risk factor for severe fetal and neonatal infections as well as preterm birth, low birth weight, and neurodevelopmental abnormalities. Current clinical interventions for GBS infection are limited to antibiotics, and no vaccine is available. We previously described VAX-A1 as a highly effective conjugate vaccine against group A Streptococcus that is formulated with three antigens, SpyAD, streptolysin O, and C5a peptidase (ScpA). ScpA is a surface-expressed, well-characterized GAS virulence factor that shares nearly identical sequences with the lesser studied GBS homolog ScpB. Here, we show that GBS C5a peptidase ScpB cleaves human complement factor C5a and contributes to disease severity in the murine models of pneumonia and sepsis. Furthermore, antibodies elicited by GAS C5a peptidase bind to GBS in an ScpB-dependent manner, and VAX-A1 immunization protects mice against lethal GBS heterologous challenge. These findings support the contribution of ScpB to GBS virulence and underscore the importance of choosing vaccine antigens; a universal GAS vaccine such as VAX-A1 whose formulation includes GAS C5a peptidase may have additional benefits through some measure of cross-protection against GBS infections.
KW - C5a peptidase
KW - Streptococcus agalactiae
KW - Streptococcus pyogenes
KW - conjugate vaccine
KW - cross-protective immunity
KW - group A Streptococcus
KW - group B Streptococcus
KW - vaccine
KW - virulence factor
UR - http://www.scopus.com/inward/record.url?scp=85180664907&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/vaccines11121811
DO - https://doi.org/10.3390/vaccines11121811
M3 - Article
C2 - 38140215
SN - 2076-393X
VL - 11
JO - Vaccines
JF - Vaccines
IS - 12
M1 - 1811
ER -