TB VACCINES:
What’s New??
Dr S G KASI
Consultant Pediatrician
Bengaluru
Existing TB Vaccine Ineffective
• BCG unreliable against pulmonary TB, which
accounts for most TB disease worldwide
• BCG is not known to protect against latent TB
• BCG is not recommended for use in infants
infected with HIV - increased risk for severe BCGrelated complications
• Despite wide use, BCG has had no apparent
impact on the growing global TB epidemic
• BCG does reduce risk of severe pediatric TB
disease, so it should continue to be used until a
better TB vaccine is available
BCG introduced in 1921
TB Vaccine Pipeline
As of November 2009
Phase I
Preclinical
Phase II
AERAS-422
VPM 1002
Hybrid-I+IC31
Aeras
Max Planck, Vakzine
Projekt Mgmt, TBVI
SSI, TBVI,
Intercell
rBCG30*
M72
UCLA, NIH, NIAID,
Aeras
GSK, Aeras
Mtb [∆lysA ∆panCD
∆secA2]
Albert Einstein College
of Medicine
MTBVAC01 [∆phoP,
∆fad D26]
AdAg85A
University of Zaragoza,
Institute Pasteur,
TuBerculosis Vaccine
Initiative (TBVI)
Hybrid-I+CAF01
HBHA
McMaster University
Phase IIb
MVA85A/
AERAS-485
Phase III
M vaccae*
Immodulon, NIH
Oxford-Emergent
Tuberculosis
Consortium
(OETC), Aeras
AERAS-402/
Crucell Ad35
Crucell, Aeras
SSI
Hyvac 4/ AERAS-404
Institute Pasteur of
Lille, INSERM, TBVI
SSI, Sanofi-Pasteur,
Aeras, Intercell
Hybrid 56
RUTI
Statens Serum Institute
(SSI), Aeras, Intercell,
TBVI
M smegmatis*
Archivel Farma
Prime
Boost
Post-infection
HG85 A/B
Shanghai H&G Biotech
Preclinical vaccine candidates are not yet in clinical trials, but have been manufactured under Good Manufacturing Practice
(GMP) for clinical use and have undergone some preclinical testing that meets regulatory standards.
*indicates candidates that have been in clinical trials in the past, but are not currently being tested in clinical trials
Source: Tuberculosis Vaccine Candidates – 2009; Stop TB Partnership Working Group on New TB Vaccines
Immunotherapy
New TB vaccines in Clinical
Development
R-BCG PRIME VACCINES:
VPM1002 rBCGDureC:Hly
• Expresses listeriolysin (Hly)
derived from Listeria
monocytogenes and enables BCG
to escape from the endosome.
• Made urease-C-deficient to
provide the optimal pH for Hly
activity .
• A Phase I clinical trial evaluating
the safety and immunogenicity of
this vaccine in healthy male
subjects has been completed
• A dose-escalation RCT (Phase
2a)comparing the safety and
immunogenicity of VPM1002 and
BCG in healthy adults in South
Africa is ongoing
AERAS-422 (rBCG)
• Genetically modify BCG such that it overexpresses one or
more major secretory proteins, early targets for the host
immune response against M Tb (antigen 85B) .
• In a Phase I RCT, rBCG30 was well tolerated and had a
comparable safety profile to nonrecombinant Tice BCG.
• Antigen 85B-specific T-cell proliferation and IFN-g ELISpot
responses were enhanced and antigen specific CD4+ and
CD8+ effector T-cell expansion was demonstrated
• The antigen 85B-specific T cells induced were also capable of
inhibiting the growth of intracellular mycobacteria
AERAS-422 (research strain AFRO-1)
• Recombinant BCG Danish 1331 strain
• Expresses perfringolysin O as an endosome escape
mechanism
• Overexpresses immunodominant and protective M.
tuberculosis antigens, 85A, 85B and Rv3407
• A Phase I clinical trial in healthy human subjects will
soon be starting in the USA
Subunit vaccines designed to
enhance BCG
• Enhance the effectiveness of BCG.
• Regimens would retain BCG vaccination of neonates
• Involve the delivery of immunodominant
mycobacterial antigens to the immune system, using:
1. Viral vectored vaccines
2. Protein – adjuvant vaccines
MVA85A
• MVA as a delivery system for the mycobacterial
antigen 85A
• Evaluated in a series of Phase I clinical trials in
healthy adults in the UK since 2002, including BCGvaccinated subjects and subjects with LTBI
• Phase I and IIa clinical trials in target populations in
South Africa, The Gambia and Senegal
• Has been safely administered to high-risk target
populations, namely HIV-infected adults, subjects
coinfected with HIV and M. tuberculosis and infants
Results of MVA85 so far…
• High frequencies of antigen-specific IFN-g-producing
polyfunctional CD4+ T cells are induced
• Expansion of a memory population
• Frequency of antigen-specific cells remains
significantly higher than baseline for at least 1 year
after vaccination
• Antigen-specific, IFN-g-producing CD8+ T cells have
also been detected
• A Phase IIb efficacy trial in BCG-vaccinated South
African infants is now underway
MVA85A in HIV+ adults
• A Phase I study evaluating the safety and immunogenicity of
MVA85A, a candidate TB vaccine, in HIV-infected adults.
BMJ Open 2011;1:e000223. doi:10.1136/ bmjopen-2011-000223
• MVA85A was safe in subjects with HIV infection,
• No clinically significant vaccine-related changes in CD4 count
or HIV RNA load in any subjects,
• Both doses of MVA85A induced an antigen-specific IFNresponse that was durable for 24 weeks,
• The functional quality of the vaccine-induced T cell response
in HIV-infected subjects was remarkably comparable with that
observed in healthy HIV-uninfected controls
MVA 85A in Infants
• Dose-Finding Study of the Novel Tuberculosis Vaccine,
MVA85A, in Healthy BCG-Vaccinated Infants. JID 2011;203:1832–43
• Infants aged 5–12 months were vaccinated intradermally with
either of 3 escalating dose schedule of MVA85A, or placebo.
• MVA85A induced potent, durable T-cell responses, which
exceeded prevaccination responses up to 168 days after
vaccination.
• Conclusions. MVA85A was safe and induced robust,
polyfunctional, durable CD4 and CD8 T-cell responses in
infants. These data support efficacy evaluation of MVA85A to
prevent tuberculosis in infancy.
MVA85 & EPI Vaccines
• Immunogenicity of the Tuberculosis Vaccine MVA85A Is
Reduced by Coadministration with EPI Vaccines in a
Randomized Controlled Trial in Gambian Infants
Sci Transl Med 22 June 2011: Vol. 3, Issue 88, p. 88ra56
• Coadministration of MVA85A with EPI vaccines was associated
with a significant reduction in MVA85A immunogenicity, but
did not affect humoral responses to the EPI vaccines
• Suggest that modifications to the standard EPI schedule may
be required to incorporate a new generation of T cell–
inducing vaccines.
AERAS-402/Crucell Ad35
• Nonreplicating adenovirus (Ad) type 35 as vector
• Expressing a fusion protein of mycobacterial antigens 85A,
85B and TB10.4
• IM administration of AERAS-402 was well tolerated and
induced polyfunctional CD4+ T cells and IFN-g-producing
CD8+ T cells in response to antigen stimulation with antigens
85A, 85B and TB10.4
AERAS-402/Crucell Ad35 2
• A Phase II trial in South Africa is recruiting HIV-infected, BCGvaccinated adults and assessing the safety (including effect on
CD4 count) and immunogenicity
• In Kenya, a Phase I and II safety, immunogenicity and efficacy
trial in BCG-vaccinated, HIV-uninfected infants is ongoing
Protein–adjuvant vaccines
• Adjuvants used may be – aluminium based compounds or
immunopotentiating agents eg, TLR ligands, saponins,
cytokines and bacterial toxins
M72
• Fusion of two proteins, Mtb32 and Mtb39,
• Formulated in the adjuvant AS02A- oil-in-water emulsion and
the immunostimulants 3-deacylated monophosphoryl lipid A
(MPL) and QS-21, a detergent purified from the bark of
Quillaja saponaria
• Well tolerated in a Phase I trial of PPD-healthy adult subjects
in the USA and induced antigen-specif ic IFN-g and IL-2
production and CD4+ T cells
• Phase IIa trials in TST-positive healthy adults in a TB-endemic
area (South Africa) and of different formulations in the
Philippines have also been completed.
Hybrid 1
• Fusion protein of antigens 85B and ESAT-6
• Hybrid 1, adjuvanted with IC31, in a Phase I trial in PPDnegative healthy adults, was associated with antigen-specific
T-cell responses. The T-cell responses were maintained for 2
years
• Hybrid 1 formulated with a novel liposomal adjuvant, cationic
adjuvant formulation (CAF01), is now in an open-label Phase I
clinical trial in The Netherlands
Therapeutic vaccines in clinical
trials
• Mycobacterium vaccae : 1 dose not very effective. 5 doses in
BCG-vaccinated, HIV-infected patients in Tanzania
demonstrated significant protection against the secondary
end point of definite (culture positive) TB, although not
against the primary end point of disseminated (bacteremic)
disease or against the other secondary end point, probable TB
• RUTI® (Archivel Farma): detoxified liposomal cellular
fragments of M. tuberculosis bacilli. In a double-blind Phase I
RCT in BCG-naive healthy men in Spain, RUTI was well
tolerated and associated with modestly enhanced responses
to PPD and mycobacterial antigens, including ESAT-6 and 85B .
THE INDIAN CONTRIBUTION…..
• Cellular Immune Responses to Nine Mtb Vaccine Candidates
following Intranasal Vaccination. PLoS ONE 6(7): e22718.
•
doi:10.1371/journal.pone.0022718, Published July 25, 2011
Suraj B. Sable, Mani Cheruvu, Subhadra Nandakumar, Sunita Sharma,et al
• In this study, a comparison of intranasal (i.n.) and
subcutaneous (s.c.) vaccination with the BCG vaccine
demonstrated that a single moderate dose delivered
intranasally induced a stronger and sustained M. tuberculosisspecific T-cell response in lung parenchyma and cervical
lymph nodes of BALB/c mice than vaccine delivered
subcutaneously.
• A Booster Vaccine Expressing a Latency-Associated
Antigen Augments BCG Induced Immunity and Confers
Enhanced Protection against Tuberculosis
Bappaditya Dey., Ruchi Jain., Umesh D. Gupta, V. M. Katoch, V. D. Ramanathan, Anil K. Tyagi
Department of Biochemistry, University of Delhi South Campus, New Delhi, India, 2 National JALMA
Institute for Leprosy and Other Mycobacterial Diseases, Agra, Uttar Pradesh, India, 3Department of Clinical
Pathology, Tuberculosis Research Center, Chennai, Tamil Nadu, India
• Evaluated the ability of a DNA vaccine expressing a-crystallina key latency antigen of Mtb to boost the BCG induced
immunity
• ‘BCG prime – DNA boost’ regimen (B/D) confers robust
protection in guinea pigs along with a reduced pathology in
comparison to BCG vaccination
• B/D immunization in mice results in a heightened frequency
of PPD and antigen specific multi-functional CD4 T cells (3+)
simultaneously producing interferon (IFN)c, tumor necrosis
factor (TNF)a and interleukin (IL)2.
Novel TB Vaccines: Cost effective?
• Cost-effectiveness of novel vaccines for tuberculosis control: a
decision analysis study. BMC Public Health 2011, 11:55
•
•
http://www.biomedcentral.com/1471-2458/11/55
Chia-Lin Tseng, Olivia Oxlade, Dick Menzies, Anne Aspler, Kevin Schwartzman
• Conclusions: Investment in an improved TB vaccine is
predicted to result in considerable cost savings, as well as a
reduction in TB morbidity and TB-related mortality, when
added to existing control strategies. For a vaccine with waning
efficacy, a prime-boost strategy is more cost-effective in the
long term.