David E. Anderson, PhD, VBI’s Chief Scientific Officer

Just as two heads are proverbially better than one, so two approaches to fighting COVID-19 are likely to double the odds of success against the virus, reasons a Cambridge, MA-based vaccine developer with key operations in Canada and Israel.

VBI Vaccines has chosen to advance two candidates from its VBI-2900 COVID-19 vaccine program into an adaptive Phase I/II study set to start by year’s end. One is VBI-2901, a trivalent pan-coronavirus vaccine candidate designed to express the Spike proteins of SARS-CoV-2, as well as SARS-CoV-1 and MERS. The other, VBI-2902, is a monovalent vaccine expressing only the SARS-CoV-2 Spike protein.

Both vaccine candidates offer the potential for single-dose vaccination—compared to the two-dose approach being pursued by several front-running COVID-19 candidates—according to preclinical results that prompted Steven Seedhouse, PhD, Vice President, Biotechnology Equity Research at Raymond James, to upgrade the firm’s rating on VBI from “outperform” to “strong buy.” Seedhouse also raised his price target from $8 a share to $9.

“This might be the best COVID vaccine,” Seedhouse declared in a research note—better than the front runner COVID-19 vaccine candidates, seven of which have received commitments totaling up to $12 billion from the Trump administration’s “Operation Warp Speed” initiative to deliver 300 million doses by January, led by Moderna (up to about $2.5 billion).

Leland Gershell, MD, PhD, Managing Director and Senior Analyst covering BioPharmaceuticals for Oppenheimer, retained the company’s “outperform” rating and $8 price target, but added in a research note: “We believe VBI’s coronavirus vaccine has potential to be best-in-class in a crowded arena and look ahead to an initiation of Phase 1/2 around YE [year-end].”

“We expect ‘2901 may be utilized in future coronavirus outbreaks, for healthcare employees, and those traveling internationally among hotspots,” Gershell of Oppenheimer wrote, whereas VBI-2902 is expected to be the company’s imminent focus for the current COVID-19 pandemic.

The accolades from analysts sparked a 32% jump in VBI’s share price the day after it was announced, to $4.25 from $3.21. Shares have slid since then to $2.91 at the close of trading September 24—more than double its $1.34 price at the start of this year, and more than five times the stock’s price the same date a year ago, when it traded at 53 cents a share.

Potential Advantages

“If the clinical data reflects what we see preclinically and you have a single dose vaccine, that certainly would confer benefits relative to having to give individuals two doses and bring them back in. So that’s one potential advantage,” David E. Anderson, PhD, VBI’s Chief Scientific Officer, told GEN.

A second advantage, says VBI, is its vaccine platform, which is based on enveloped virus-like particles (eVLPs) that are designed to mimic the structure of viruses. According to the company, the structural similarity between viruses in nature and target proteins expressed in an eVLP enable eVLP vaccines to confer greater immunity compared with vaccines using the same recombinant target protein alone.

“We have data from a previous program, prophylactic CMV [cytomegalovirus candidate VBI-1501, which has completed Phase I], which demonstrated that compared to a recombinant protein, if you put the same amount of protein but presented on the surfaces of these eVLPs, you really enrich for neutralizing antibody activity,” Anderson said. “That’s one of the reasons we felt we needed to get into the [SARS-CoV-2] space, because we thought it just was so well suited for the technology.”

Another potential advantage to VBI’s vaccines, Anderson said, is the broader immunity its trivalent candidate would enable—no small consideration given how SARS-CoV-2 has presented multiple strains since it first emerged in Wuhan, China—at least six strains, according to a study published July 22 in Frontiers in Microbiology by Daniele Mercatelli, PhD, and Federico M. Giorgi, both of the University of Bologna in Italy.

“Either you update your vaccine to represent new strains every year—like you do for influenza, another RNA virus—or you induce a vaccine that can broaden that response, and it gives you long-term protection, because it’s got more broad reactivity,” Anderson said. “I think that’s really going to be the challenge for us, to see if you can share that broadened response with the trivalent candidate. The data that we’ve disclosed is certainly early, but I think it’s definitely supportive of that potential.”

VBI will try to augment that broadened response, he added, by testing convalescent sera against new variances in strains of SARS-CoV-2 as they emerge over time.

Canadian Contribution

Among believers in VBI’s vaccines is the government of Canada, where VBI bases some 40-45 staffers at an R&D facility in Ottawa. On September 16, according to a regulatory filing, Canada agreed to contribute to a Canadian subsidiary of VBI C$55.986 million (about $42 million) or about 75% of the company’s costs, whichever was less, toward developing the trivalent vaccine and/or the monovalent vaccine through Phase II studies to be conducted exclusively in Canada in or before the first quarter of 2022.

Canada’s National Research Council (NRC) earlier this year partnered with VBI on the selection of COVID-19 candidates. VBI and the NRC had teamed up several years earlier when the company began developing its preclinical eVLP-based Zika virus vaccine candidate VBI-2501.

“It really plays to the strengths of both parties, where we design the vaccine candidates, they run the preclinical immunogenicity studies, they develop the assays to measure and test the neutralizing activity using infectious viruses,” Anderson said. “It has just worked out very well, and that, I think, has helped us speed things along. We’ve been able to focus on production and purification, and get the materials to them so they could run the animal studies.”

As part of its collaboration with VBI, the NRC carried out three preclinical mouse studies designed to enable selection of optimized clinical candidates.

Convalescent sera from 20 individuals who had contracted and recovered from COVID-19 were collected for comparison. The sera were classified according to participants with a high-titer, robust response to the infection and those mounting a low-titer, weaker response. Neutralizing activity was quantified using the most stringent 90% plaque reduction neutralization assay (PRNT90).

The preclinical studies showed both VBI-2901 and -2902 generating strong data, VBI said in August. The studies assessed antibody binding titers and neutralizing antibody titers across a number of vaccine constructs, comparing VBI’s proprietary enveloped virus-like particle (eVLP) platform to recombinant vaccine candidates, differences in the conformation of the spike protein, and a variety of adjuvants.

Surpassing Sera

After a single dose, VBI’s eVLPs which expressed a stabilized pre-fusion form of the COVID-19 spike protein elicited a neutralizing antibody geometric mean titer (GMT) that was four times higher than the 1/40 GMT of high-titer convalescent sera. GMT increased to 64 times higher than convalescent sera after a second dose, VBI reported. Induction of neutralizing antibody titers further improved approximately 5-fold following use of a variety of adjuvants that also promoted strong Th1-type antibody and T cell responses.

Those eVLPs also induced, after a single dose, an antibody binding GMT that was 10 times higher than both the GMT of high-titer convalescent sera and the GMT induced with a stabilized pre-fusion recombinant spike protein.

“If you look at preclinical data from multiple vaccine companies, it takes about two doses to get on par or maybe slightly above convalescent sera. We achieved that with a single dose with our monovalent construct,” Anderson said.

The trivalent construct further induced antibody binding titers across COVID-19, SARS, and MERS Spike proteins, and also broadened reactivity to a seasonal human coronavirus not expressed in the vaccine.

“Given the strength of that and given how straightforward it would be to move that into the clinic as quickly as possible, we felt we needed to advance that as fast as we can,” Anderson added.

To advance the vaccine candidates into clinical studies, VBI signed a manufacturing agreement in August with Therapure Biomanufacturing, an integrated CDMO based in Mississauga, ON. Under the agreement, whose value has not been disclosed, Therapure agreed to oversee biomanufacturing of the vaccine drug substance as well as the aseptic fill of the drug product at its Mississauga facility.

Pipeline Plans

In addition to its candidates for COVID-19, CMV, and Zika, VBI’s pipeline includes lead candidate Sci-B-Vac®, the company’s tri-antigenic prophylactic hepatitis B (HBV) vaccine; clinical-phase vaccine candidates for therapeutic hepatitis B (VBI-2601) and glioblastoma multiforme (VBI-1901); and a preclinical vaccine candidate for medulloblastoma (VBI-2701).

By year’s end, VBI is expected to release initial human proof of concept data from an ongoing Phase Ib/IIa trial of VBI-2601, which is being co-developed with Chinese biopharma Brii Biosciences; as well as initial immunologic and tumor response data from a Phase IIa trial of VBI-1901 with AS01B adjuvant.

Anderson said VBI plans during the fourth quarter to file for a BLA in the U.S., and a Marketing Authorisation Application in Europe, for Sci-B-Vac.

Canaccord Genuity has projected U.S. peak sales for Sci-B-Vac of about $125 million by 2025, as well as partnerships in the U.S. and Europe that would result in royalties for VBI, the firm’s John Newman, PhD, CFA, Managing Director, Biotechnology, wrote last month in a research note.

VBI finished Q2 with a net loss of $9.5 million, compared with a $13.2 million net loss in the year-ago quarter—as well as $61 million in cash and cash equivalents and another $25 million in short-term investments. The company raised $57.5 million gross proceeds in an underwritten public offering in April, and the following month secured an up to $50 million debt financing with K2 HealthVentures, and repaid $15.3 million in debt to Perceptive Credit Holdings.

Expectation of Approvals

Newman has maintained Canaccord Genuity’s “Buy” rating on VBI and $3 price target based on expectations of U.S. and European approvals for Sci-B-Vac during 2021.

VBI will base its regulatory filings for Sci-B-Vac on positive late-stage data the company presented in late August. The data showed that Sci-B-Vac met its endpoint in the Phase III CONSTANT trial (NCT03408730) by showing consistency of immune response as measured by the geometric mean concentration (GMC) of hepatitis B antibodies (anti-HBs titers) across three consecutively-manufactured lots of vaccine.

Sci-B-Vac also met its primary endpoint in another Phase III trial, PROTECT (NCT03393754) by inducing more immunogenic response across a greater proportion of subjects compared to GlaxoSmithKline’s Engerix-B® [Hepatitis B Vaccine (Recombinant)]. The trial defined immunogenic response as anti-HBs titers ≥ 100 mIU/mL.

Timo Vesikari, MD, PhD, principal investigator of the PROTECT and CONSTANT trials, presented results from both trials at the Digital International Liver Congress™ 2020 (ILC), the Annual Meeting of the European Association for the Study of the Liver (EASL), held August 27-29. Vesikari is Professor Emeritus and Director of the Nordic Vaccine Research Network in Finland.

“What makes Sci-B-Vac different is that it has two additional antigens relative to traditional hepatitis B vaccines. We think those two antigens can be particularly advantageous in a therapeutic setting,” Anderson said.

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