Hi @availlant @john.tavis
I recently saw VBI updates on the BRI therapeutic vaccine update. Any good update from the meeting which was on 18th feb? Did they acheived the goal of functional cure or far from it?
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Dear @Ash_Malhotra ,
I think its important to understand the fundamental problem with the approach of therapeutic vaccination. HBV infection in any one individual consists of thousands of quasispecies. These quasispecies develop because of the highly error prone nature of the HBV enzyme which produces frequent random mutations in mature viral genomes. Resistant quasispecies can become dominant in the cccDNA and integrated HBV DNA pool (and also in the viruses and SVP produced) in response to immune pressure or direct acting antiviral approaches.
VBI-2601 is indeed the best of the therapeutic vaccines designed to date and is uses as its antigen SVP (instead of HBsAg in a suboptimal antigenic context found in earlier vaccines). However, it uses only one species of HBsAg and thus generates immune responses which the viral infection has already learned to escape from.
In the previously published phase II study of VBI-2601 in monotherapy, large amounts of anti-HBs were produced but there was no effect on circulating HBsAg - becuase the anti-HBs produced did not recognize the circulating HBsAg quasispecies which are already mutated to escape the host immune response.
At APASL earlier this month, data from a combination study with a siRNA (VIR-2218 aka ALN-HBV aka BRII-825) with this same VBI-2601 vaccine (aka BRII-197) was presented. Despite numerous boosts with this vaccine and strong production of anti-HBs, there was no improvement on the moderate HBsAg responses observed with BRII-825 in monotherapy.
Best regards,
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Just a bit of followup from the basic science perspective.
It will be quite important in my opinion to drop the HBsAg levels in the serum before attempting therapeutic vaccination. siRNAs, antisense RNAs, and Andrew’s NAPs can do that. The reason is that the immune system has been swamped by exceptionally high concentrations of HBsAg for decades in chronically infected patients. That triggers a non-responsive state in the immune system, sometimes called anergy. Animal models indicate that therapeutic vaccination can get around the anergy issue.
The genetic diversity and mutability issues that Andrew raises are important. Note that it is not clear that HBV forms a true quasispecies, which has a very specific evolutionary meaning, but it is certainly true that the intra- and inter-person diversity is biologically very significant, so this issue is just semantics in relation to therapeutic vaccine development. Regardless, this genetic diversity problem is much less of an issue for HBV than it is for many other viruses (especially HCV and HIV). This is primarily because the dominant neutralizing epitope on HBsAg (the “a” epitope) is remarkably conserved in HBV and hard to change without harming the fitness (ie, “health”) of the virus. So HBV’s genetic diversity is certainly a problem, but it should be surmountable as drug development proceeds.
Overall, I am very excited about the possibility of therapeutic vaccination being a major player in the eventual HBV cures that are under development. I never thought I’d say that because I’ve watched the field for >30 years, and for the vast majority of that time therapeutic vaccination kept failing badly. Advances in viral control and understanding of vaccination strategies changed the landscape in an exiting way.
John.
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Some counterpoints to John’s comments from the clinical literature.
HBsAg declines with ASO / siRNA are qualitatively different from that observed when functional cure is achieved with NUC therapy (very rare), pegIFN (infrequent) or with NAPs (more frequent).
In the case of compounds designed as ASO or siRNA, the clinical evidence clearly indicates that mRNA degradation is largely absent with these compounds. This has been formally proven in animal models which correctly model the genetic plasticity of HBV infection where rapid evolution of escape mutants to ASO and siRNA have been described (within 4 weeks). We also see these ASO / siRNA escape quasispecies present in a significant proportion of the quasispecies pool before therapy with these agents even begins. These escape quasispecies are likely present in some small proportion in the majority of patients. This is why with siRNA and ASO approaches either avoiding accumulation in immunoreactive cells or being devoid of immunoreactive properties, little to no HBsAg response is observed and importantly, rapid rebound of initial antiviral response to baseline levels is observed (again within 4 weeks). Unfortunately, these important studies are frequently forgotten (as are the fundamental principles by which ASO / siRNA function and normally manifest in clinical practice). Antiviral responses with ASO or siRNA are only observed when these compounds contain immunostimulatory properties and also accumulate in immunoreactive cells of the liver (which are not infected). This results in a HBsAg response which becomes saturated at levels still leaving large amounts of HBsAg untouched (likely produced from integrated HBV DNA, a HBsAg reservoir which is not affected by the well described off target stimulation of innate immunity with these compounds). A good resource for understanding these limitations can be found here.
On the other hand, HBsAg loss leading to functional cure during the natural history or therapy of HBV with NUCs, pegIFN or NAPs always involve clearance of HBsAg to undetectable levels (typically 1000 fold greater reduction than possible with ASO or siRNA).
On the issue of quasispecies there is a well developed body of literature which describes the co-existence of numerous HBV quasispecies within any one individual and the ability of these species to rapidly change in their proportion during the natural history of the disease or antiviral therapy, including in the “a” determinant. Some examples are found here, here, here, here, here, here, here, here and here.
As John rightly states, HBsAg mutation in order escape immune detection by the existing immune repertoire can alter secretion efficiency of both virus and subviral particles but they do not result in complete loss of viral and subviral particle secretion. This is one the fundamental principles underlying the problem of escape from birth dose vaccination following maternal transfer (see here).
I agree that that therapeutic vaccination is an avenue on which more research needs to be done but the failure of the designs of the latest vaccines (e.g. VBI-2601) shows that the way in which we approach the implementation of vaccination needs to change. Despite the stimulation of strong HBsAg specific T-cell and B-cell function by VBI-2601 and the production of high titers of anti-HBs, none of these had any impact on the circulating HBsAg which is present and not recognized by these newly engendered immune activities. All current therapeutic vaccines in development employ a similar approach with a single HBsAg antigen so will suffer the same fate. Vaccines are needed with a diverse HBsAg antigen population which stimulates a much more diverse immune repertoire of HBsAg specific immune function capable of targeting the diverse circulating HBsAg present.