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A therapeutic vaccine for chronic hepatitis B

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 2R44AI088919-06A1
Agency Tracking Number: R44AI088919
Amount: $1,737,018.00
Phase: Phase II
Program: SBIR
Solicitation Topic Code: R
Solicitation Number: PA18-574
Timeline
Solicitation Year: 2018
Award Year: 2019
Award Start Date (Proposal Award Date): 2019-09-05
Award End Date (Contract End Date): 2021-08-31
Small Business Information
3030 BUNKER HILL ST STE 350
San Diego, CA 92109-5757
United States
DUNS: 160242579
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 DAVID MILICH
 (858) 581-3960
 dmilich@vrisd.org
Business Contact
 JOYCE JONES
Phone: (858) 581-3960
Email: jjones@vlp-biotech.com
Research Institution
N/A
Abstract

Project Summary/AbstractAlthough a safe and efficacious preventative vaccine for HBV has been available for 30 years, it is not
effective against chronic infection. The primary cause of chronic HBV (CHB) and the greatest impediment to
developing a therapeutic vaccine is the direct and indirect effects of immune tolerance, primarily of CD4+ T
cells, to HBV antigens. The resulting defective CD4+/CD8+ T cell response, poor cytokine production,
insufficient neutralizing antibody (nAb) levels and poor response to conventional HBsAg vaccination
characterize CHB infection.The objective of this revised SBIR Phase IIB continuation of R44 AI088919-06 proposal is to fully develop
the use of virus-like particles (VLPs) to elicit nAb to prevent viral spread and prime CD4+/CD8+ T cells to
eradicate intracellular HBV. For this purpose, in Phase I and II studies we have defined 8 neutralizing B cell
epitopes from the HBV envelope PreS1 region, which were consolidated and inserted onto a species variant of
the HBV core protein, namely the woodchuck hepatitis core antigen (WHc). PreS1 B cell epitopes were chosen
because of their preferential expression on HBV virions as opposed to subviral particles. We chose the WHc
as a vaccine carrier because the WHc and HBc are not cross-reactive at the B cell level and, just as
importantly for our purposes, are only partially cross-reactive at the CD4+/CD8+ T cell level. Therefore, CD4+ T
cells specific for WHc-unique T cell sites provide cognate T-B cell help for anti-PreS1 Ab production and are
not curtailed by immune tolerance. In fact, in Phase II studies in HBc- and HBV-Tg mice, which are tolerant to
HBc, immunization with hybrid PreS1-WHc VLPs elicited equivalent levels of high titer anti-PreS1 nAbs in
wildtype and Tg mice. To determine the capacity of the anti-PreS1 nAbs to prevent an acute HBV infection and
inhibit viral spread in an established infection, we showed that passive transfer of PreS1 nAbs into human-liver
chimeric mice prevented acute infection and cleared serum HBV from mice previously infected with HBV (i.e.,
a model of CHB). At the T cell level, PreS1-WHc VLPs and WHc-based DNA immunogens elicited HBc-speciic
CD4+ Th and CD8+ CTL responses.For the current proposal in Aim 1, we will select the final PreS1-WHc VLP candidate combination. To target
intracellular HBV, in Aim 2 we will produce WHc-based DNA(RNA) constructs that circumvent immune
tolerance and elicit CTL to the HBc and HBs. Expression of the HBc and HBs within the WHc VLP will allow
WHc-specific (heterologous) CD4+ T cells to “help” HBc/HBs-specific CTL thus bypassing impaired
homologous T cell help as already demonstrated for PreS1-specific B cells. In Aim 3, the efficacy of VLP-
DNA(RNA), prime-boost vaccine candidates will be evaluated in HBV-Tg mice and in an HBV-specific adeno-
associated (AAV-HBV) infectious system, both models of immune tolerance and chronic HBV infection. In Aim
4, the WHc VLP production and purification will be optimized for transfer into a CMO or partner’s facility for
scale up.Project Narrative
It is estimated by the WHO that worldwide more than 240 million people are chronically
infected with the hepatitis B virus (HBV) and approximately 20-40% will develop serious
complications such as cirrhosis, liver failure and hepatocellular carcinoma. Although a safe
and effective preventative vaccine for HBV is available, it is not effective against chronic
infection. The existing treatments for chronic infection are unsatisfactory for a number of
reasons. This is a proposal to develop virus-like-particles (VLPs) capable of eliciting
neutralizing anti-HBV antibodies and priming CD4+/CD8+ T cells reactive with HBV antigens
as a candidate therapeutic vaccine for chronic HBV infection.

* Information listed above is at the time of submission. *

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