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Anti-Chlamydia Vaccine:From Bench to Bedside
Ashlesh Murthy, M.B.B.S., Ph.DResearch Assistant Professor
University of Texas at San Antonio
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Chlamydia
Obligate intracellular pathogen
C. trachomatis, C. pneumoniae, C. psittaci, C. pecorum, C. muridarum
C. trachomatis multiple serovars: A-K, L1-3
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Chlamydia trachomatis Infections
Trachoma and Inclusion Conjunctivitis
Serovars - A, B, Ba, C
LymphoGranuloma Venereum
Serovars - L1, L2, L3
Urogenital InfectionsSerovars - D, Da, E, F, G, Ga, H, I,
J, K
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Global Prevalence of Chlamydial STD
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Chlamydial STD
Adapted from
http://www.cdc.gov/std/stats/tables/table1.htm
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006
0. 40
0. 60
0. 80
1. 00
1. 20
(Million
s)
New Cases Of Chlamydia Reported Per Year In USA
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Chlamydial STD-Ascending Infection
Eskilsden and Gupta et al., In Revision
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Vaginitis
Cervicitis
Endometritis
Salpingitis
Chlamydial STD-Ascending Infection
PID
No Symptoms
Antimicrobials
Dye alone
Dye+Chlamydia
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NormalPelvic Inflammatory Disease
Ectopic pregnancy
Infertility
Chlamydial STD-Reproductive Damage
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90 million cases
50-70% of patients initially asymptomatic: not treated
40% of untreated females – pelvic inflammatory disease
20% of PID cases- infertility
Adapted from www.cdc.gov- 2006 STD statistics
Chlamydial STD- Statistics
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Anti-Chlamydial Vaccine
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Goals for Chlamydial Vaccine
Infection
Symptoms (25%)
No Symptoms (75%)
Transmission
Sequelae
Prevent infection (Sterilizing immunity)- ideal
Reduce transmission / Duration of shedding- practical
Prevent pathological sequelae
Protection against multiple serovars
Re-Infection
Immunity
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Chlamydial Vaccine Trials of 1960s
Formalin-killed whole chlamydial organisms
Reduction in incidence for ~ 1 year
Comparable/exaggerated ocular pathology in vaccinees
Focus on sub-unit vaccines
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Chlamydial Developmental Cycle
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Vaccines Against Chlamydial STD
Major outer membrane protein (MOMP) Chlamydia-purified MOMP Recombinant MOMP MOMP DNA MOMP synthetic peptides MOMP plus outer membrane protein 2 (omp2) Chlamydia-purified MOMP refolded to native configuration
Cons: MOMP - serovar-specific
Currently no licensed vaccine against C. trachomatis
Need for identification of new vaccine candidates
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Chlamydial Developmental Cycle
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Chlamydial Protease-Like Activity Factor (CPAF)
Nucleus
Inclusion
CPAF
Overlay
Secreted into host cytosol
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CPAF-Human Antibody Responses
Sharma et al., Infect Immun. 2006
0
1
2
N ega tive Pos itive
C hlamydia Infec tion H is tory
A nti-C PAF IgG
Ab
sorb
an
ce
(6
30
nm
)
CPAF
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CPAF-Highly Conserved
Dong et al., Infect Immun. 2005
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CPAF- A Potential Vaccine Candidate
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Mouse Model of Chlamydial Infection
Days after challenge0 30 80
Vag
inal
chl
amyd
ial s
hedd
ing
Oviduct dilatation
106
C. muridarum
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Day –1: IL-12 (0.5 mg)
Day 0:rCPAF(15mg)+ IL-12 (0.5 mg)
Day +1: IL-12 (0.5 mg)
Day 28: rCPAF (15 mg)+ IL-12 (0.5 mg)
Day 14: rCPAF (15 mg)+IL-12 (0.5 mg)
Day 60: 5X104 IFU C. muridarum
Estimation of bacterial shedding
Examination of disease pathology
Intranasal
Vaginal challenge
Protocol For Vaccination Studies
Recombinant CPAF from C. trachomatis L2cloned into E. coli
30 day Rest
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Early Responses to Immunization
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CPAF Vaccine : Robust IFN-g Response
Murthy et al., Infect Immun. 2007
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CPAF Vaccine: Systemic Antibodies
Murthy et al., Infect Immun. 2007
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CPAF Vaccine: Mucosal Antibodies
Murthy et al., Infect Immun. 2007
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CPAF Vaccine: Chlamydial Clearance
Murthy et al., Infect Immun. 2007
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CPAF+IL-12: Prevents Hydrosalpinx
Murthy et al., Infect Immun. 2007
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CPAF Vaccine: Preserves Fertility
Murthy et al., In Review, 2010
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Role of Human HLA-DR
Murthy et al., Infect Immun. 2006
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Minimal Role for Antibody
Murthy et al., FEMS Immunol. Med. Microbiol. 2009
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Role of CD4+ T-cells
CD4+ T cell adoptive transfer
Murphey et al., Cell. Immunol. 2006
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Role of IFN-g
Murthy et al., J. Immunol. 2008
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Summary
CPAF vaccine administered with Th1 adjuvant:
Enhances clearance of infection Protects against severe pathology Induces robust cellular IFN-g response Induces systemic and mucosal antibody
Protection is dependent upon CPAF-specific cellular IFN- g responses but not antibody
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Ongoing Collaborative Effort
US Patent Application No. 12/243,769: Inventors- Arulanandam, Murthy, Zhong
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Bench to Bedside
Anti-Chlamydia vaccine
Vaccine antigen discovery
Identification of pathogenic
mechanisms
Validation of protection and pathogenesis
correlates in clinical samples
Routes, Delivery systems
Non-Human Primates
Clinical Trials
Adjuvants, Formulations
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Bernard Arulanandam, Ph.D., M.B.A.
Weidang Li, M.D., Ph.D.
Bharat Chaganty, MS
Sangamithra Kamalakaran, B.Tech
Kishan Evani, MS
Rishein Gupta, Ph.D.
Yu Cong, M.D.
Madhulika Jupelli, Ph.D.
Cathi Murphey, M.S.
Acknowledgements
Guangming Zhong, M.D., Ph.D., UTHSCSA
M. Neal Guentzel, Ph.D., STCEID, UTSA
Aruna Mittal, Ph.D, IOP, India
1R03AI088342
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