Shooting for the Universe

Biopharmaceutical Report III


Issue16_April 2018




SHOOTING FOR THE UNIVERSE

By Michael Leviten, Senior Writer


CureVac AG is bringing a new modality to the race for a universal flu vaccine with an mRNA program backed by a grant from the Bill & Melinda Gates Foundation. While the company believes its approach can yield a product with a cost structure and supply chain relevant for the developing world, it faces a steady pipeline of clinical compounds based on conventional modalities. Last week, CureVac announced it received backing from Gates for a universal flu vaccine and a vaccine against malaria. The funding comes three years after Gates made a $52 million equity investment in CureVac to support development of the company’s RNA platform and construction of an industrialscale GMP facility.


Daniel Menichella, CBO of CureVac and CEO of its U.S. CureVac Inc. subsidiary, told BioCentury the company expects to select a clinical candidate by the end of 2020, and said Gates’ help goes beyond funding and includes coordination with academics that could help selection of an optimal vaccine design. He would not disclose the amount of either of the new grants, although he told BioCentury the flu vaccine award is “sizable.” The need for a universal flu vaccine has been heightened by this year’s harsh flu season. According to the CDC, the current vaccine provides only 36% protection. A Feb. 15 statement from FDA Commissioner Scott Gottlieb highlighted the challenges of depending on seasonal vaccines, which include prediction of which strain will be dominant, the ability of the virus to mutate as it circulates, and efficacy differences among different manufacturing approaches. For example, for unknown reasons, cell-based vaccines against the H3N2 strain provided better protection than egg-based vaccines this year.


Momentum for moving away from seasonal vaccines is starting to mount. “Ultimately, developing a universal flu vaccine that provides protection against many different strains of flu from year-to-year would be ideal,” wrote Gottlieb, although he noted that such a solution is likely “several years away.” On the same day, Sen. Ed Markey (D-Mass.) introduced a bill to make a $1 billion commitment to NIH over five years for research towards a universal influenza vaccine, with the goal of creating lifetime protection from the disease. NIH’s National Institute of Allergy and Infectious Diseases (NIAID) has a universal flu vaccine in Phase I testing, and at least 10 companies and institutions outside of CureVac have universal flu vaccines in preclinical to Phase II testing (see “An Expanding Universe”). NIAID Director Anthony Fauci told BioCentury the key is to create a product that induces an immune response against the conserved region of the virus that isn’t subject to season-toseason change.


“A universal vaccine would prevent the need for a new vaccine every year to accommodate genetic drift and protect us from the emergence of a pandemic strain,” said Fauci. While there is no consensus on the best region to target, most approaches leave out or use weakly immunogenic versions of the rapidly mutating head region of influenza HA. The HA head normally dominates the immune response and occludes response to other, more broadly conserved regions of the protein. The products in development are protein, peptide or synthetic DNA in nature. CureVac believes that its RNA product can have advantages in price and CMC that make it competitive, said Menichella.


Gates did not respond to requests for an interview. On its website it stated that its focus for the CureVac relationship is to “leverage the mRNA platform to significantly reduce timelines and manufacturing cost involved in developing thermostable vaccines against the foundation’s target diseases.” Gates has given four other R&D grants that specify universal flu vaccines, and a fifth to form a consortium of funders for advancing development of a universal flu vaccine.


MODALITY MOVE


Menichella said CureVac has produced a lyophilized RNA formulation, paving the way for a heat-resistant vaccine that could avoid the need for cold chain distribution. He would not comment on the costs of producing other types of vaccines, but said the RNA approach is “extremely cost effective. The vial costs more than the vaccine inside,” he told BioCentury. The terms of the 2015 agreement with Gates require CureVac to make funded products available “at an affordable price in poor countries.” The company will be able to market the products in developed countries either by itself or through licensees. Fauci told BioCentury that the new modality adds to the field. “It’s too early to pass any judgment on the best way to make a vaccine but RNA vaccines are a new platform. It’s an interesting platform for vaccines and we always welcome new approaches.”


Fauci noted RNA vaccines are still an unknown quantity because they are not yet on the market. CureVac has at least 8 RNA-based preventative vaccines in development; the most advanced, CV7201, is in Phase I to prevent rabies. Still, Fauci thinks there are specific advantages to the modality. “RNA is relatively easy to scale up quickly and there is a degree of precision about it,” he told BioCentury. David Vaughn, director, R&D, GSK vaccines at GlaxoSmithKline plc, agreed that the CMC advantages could make a difference. “In terms of a nucleic acid vaccine approach the huge advantage is speed,” said Vaughn.

He cited a publication that used GSK’s self-amplifying mRNA system to take a sequence for an H7N9 strain that produced an outbreak in China in 2013 and create a vaccine that was ready for testing in mice within eight days. He said GSK is interested in nucleic acid vaccines, which he thinks represent a “true rapid response technology” and could be an intermediate step in the quest for a universal vaccine. According to Vaughn, the pharma is working on a vaccine that is stable at room temperature, and plans to develop one that can remain active at 30°C for use in African nations.


UNIVERSAL RACE


The search for a universal flu vaccine dates back over a decade, and has been hampered by technical challenges such as production of a recombinant version of the conserved HA stem, and finding other conserved regions to target. CureVac is not disclosing which antigenic regions it’s focusing on or other molecular details of its flu vaccine. The most advanced compound in development is M-001 from Biondvax Pharmaceuticals Ltd., which is slated to enter Phase III testing this year. M-001 is a fusion protein that strings together triplicates of nine peptides from conserved regions of three flu proteins, HA, M1 and NP, and excludes the HA head region. Within the fusion protein, the peptides are separated by a single amino acid that introduces a kink to promote an immune response to each.

According to Joshua Phillipson, business development manager at BiondVax, the vaccine elicits both cellular and humoral responses and has been tested in almost 700 subjects in trials in Europe and Israel. Phillipson said the company is planning a Phase III trial in Europe and Phase II trial in the U.S. The U.S. study will be conducted in collaboration with NIH. Two candidates are in Phase II trials: FLU-v from Imutex Ltd. and MVA-NP+M1 from Vaccitech Ltd. Flu-v is a peptide vaccine that targets T cell responses to a trio of influenza proteins — NP, M1 and M2. Vaccitech’s candidate is an adenoviral vaccine that includes NP and M1 sequences, and uses a prime boost strategy to stimulate cellular and humoral responses. NIAID’s Phase I candidate is a “headless” HA vaccine that targets the protein’s stem region.


According to Fauci, HA’s stem has arisen as one of the most promising targets for eliciting a broad immune response. “Over the last decade or so we found there were these crossreactive stem responses, but, sometimes people didn’t pay much attention to them because they weren’t very powerful,” he said. NIAID’s recombinant HA stem is meant to harness that broad response and make it stronger by avoiding exposure to the protein’s head.


NIAID researchers have published animal data showing the nanoparticle-loaded stem protein vaccine can induce immune responses, reduce viral titers and protect mice from weight loss and a lethal challenge. GSK has three potentially universal vaccines in Phase I testing that employ both heads and stems. The vaccines, which were developed at Icahn School of Medicine at Mount Sinai, use chimeric viruses with “exotic” and poorly immunogenic head regions from rare flu viruses, such as H5, 7 or 8, fused to an H1 stem. The approach involves a heterologous vaccination strategy that alternates the head regions in the vaccine but keeps the stem constant so only the stock response becomes amplified. Each of GSK’s Phase I candidates contain a different head region. Florian Krammer, associate professor of microbiology at Icahn, told BioCentury the strategy protected mice from at least six different HA variant strains.



“RNA is relatively easy to scale up quickly and there is a degree of precision about it.”

Anthony Fauci, NIAID



However, Sanofi SVP of Vaccine R&D John Shiver is skeptical about the preventive potential of vaccines designed for the stem response. “They’re more likely to protect from the more severe consequences of flu rather than the less severe ones or blocking infection. That doesn’t mean there’s no role for those types of antigens but that’s not what current flu vaccines are expected to do,” he told BioCentury. Sanofi has a preclinical universal flu vaccine program, and is using computational methods to find conserved regions of flu proteins to target. Fauci noted that these first wave vaccines are likely to provide broader coverage than the current approach but may not result in full universality. “I look at it as a gradually improving iterative process. So there will be a universal flu vaccine 1.0 which means it won’t protect against all influenza but maybe all H3N2s.That’s the first goal I’d like to achieve – getting it against all H3N2s – that would be really good,” he said.




------------COMPANIES AND INSTITUTIONS MENTIONED-----------------------------------------------

Bill & Melinda Gates Foundation, Seattle, Wash.

BiondVax Pharmaceuticals Ltd. (NASDAQ:BVXV), Ness Ziona, Israel

CureVac AG, Tübingen, Germany

GlaxoSmithKline plc (LSE:GSK; NYSE:GSK), London, U.K.

Icahn School of Medicine at Mount Sinai, New York, N.Y.

National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, Md.

National Institutes of Health (NIH), Bethesda, Md.

Sanofi (Euronext:SAN; NYSE:SNY), Paris, France

Vaccitech Ltd., Oxford, U.K.


------------TARGETS AND COMPOUNDS----------------------------------------------------------------------

HA - Influenza A virus hemagglutinin

M1 - Influenza A virus matrix protein M1

M2 - Influenza A virus matrix protein M2

NP - Influenza A virus nucleoprotein


------------REFERENCES-------------------------------------------------------------------------------------------

Giles, B., et al. “A computationally optimized broadly reactive antigen (COBRA) based H5N1 VLP vaccine elicits broadly reactive antibodies in mice and ferrets.” Vaccine (2011)

Leviten, M. “Neutralizing the flu.” BioCentury Innovations (2016)

Magini, D., et al. “Self-Amplifying mRNA Vaccines Expressing Multiple Conserved Influenza Antigens Confer Protection against Homologous and Heterosubtypic Viral Challenge.” PLoS One (2016)

Nachbagauer, R., et al. “A universal influenza virus vaccine candidate confers protection against pandemic H1N1 infection in preclinical ferret studies.” Vaccines (2017)

Yassine, H., et al. “Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection.” Nature Medicine (2015)


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