Vaccines 2016: Big Bets for Global Threats

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The Zika virus outbreak has given us the photogenic image of the year. Pictures of newborns with microcephaly have provoked horrors in the public’s imagination in a way that few things outside of tropical jungles and insidious targeting of the unborn can.

The jungles of South America remain shadowy and treacherous, but the potential for insect-borne maladies of rainforest derivation striking urban populations, even at non-tropical latitudes, is more of a possibility than ever given global trade and travel. 

Like the jungle itself, the Zika virus is shrouded in mystery. Its method of transmission, level of virulence, and the primer for the long-known virus’ recent and epidemic ascent are still unclear. Meanwhile, the precise link to birth defects remains speculative while researchers search for a causative connection and comb for potential secondary factors. What is clear is that Zika has grabbed the attention of the populace. Media and state agencies will continue to report and prey on a frightened public, as will conspiracy theorists. And with more frightening pictures to come, the global 24-hour news cycle will keep a close eye on just how far the Aedes aegypti and Aedes albopictus mosquitoes manage to fly this summer.

Need for speed

With the drama of a potential global epidemic as background, biopharma firms have sprung into action. Sanofi’s vaccine division, Sanofi Pasteur, announced that it would lead the way against Zika. Given its recent successes launching the dengue fever vaccine Dengvaxia, the French giant hopes its recent experiences can be beneficial to expedite Zika vaccine development as rapidly as possible. Zika is “dengue-like,”noted Jim Tartaglia, VP for new vaccine development at Sanofi Pasteur, so the firm will look to leverage its proven vaccine technology for dengue, and other flaviviruses, toward Zika, and will also look to apply what it learned developing its dengue vaccine

Big Pharma, along with government agencies and the non-profit ecosystem that targets diseases in the developing world, will bring significant resources to bear in the coming months and years. But truly accelerated progress might require more than partnerships and funding. The World Health Organization (WHO) has reported that about 15 groups and/or companies are working on a Zika vaccine, though the effort is dispersed and in its infancy. The world’s vaccine and drug developers, along with government agencies, are struggling to answer the needs for more responsive capabilities when it comes to responding to disease outbreaks. Important lessons have been learned from the response to last year’s Ebola virus pandemic as well as how the industry and various stakeholders have engaged and aligned around HIV, Tartaglia explained.

“I believe there will be rapid development of vaccine candidates for Zika,” noted Lynlee Burton, director of project delivery, vaccines, with PRA Health Sciences. It remains to be seen how strong a response researchers can get from early products, but based on experience with clinical development for Ebola treatments, leveraging of data to expedite the process and the willingness of collaborators and regulators to fast track clinical steps will be paramount.

With Ebola, the industry saw a willingness to move forward with successive trials before full data analysis from preliminary safety studies were completed. Zika doesn’t confront researchers with the same level of lethality, but the mania around it will facilitate a similar sense of haste to advance development stages before every last “i” is dotted or “t” is crossed. Additionally, the clinical trial industry is notoriously slow-mired in decades-old technology and bottlenecks around steps like data transfers. “But our ability to get data in-house, cleaned, and in place to facilitate decision making is greatly improved,” Burton explained. Certainly, one can hope that modernized and efficient clinical testing practices will be utilized fully with modern IT systems; waiting for fax machines to transmit will not be accepted practice.

Unfortunately, the fact that Zika is generally a mild disease, and many infected individuals don’t even know they have it, makes accurate detection and diagnoses essential. Developing a vaccine and determining efficacy and safety for a disease that moves through the human population with such stealth will be tough. This is not something that’s killing adults, and the congenital defects are occurring at an unknown percentage, added William B. Smith, professor of medicine, University of Tennessee Medical Center. 

The most prone population  appears to be pregnant women and the unborn fetus; so researchers face the difficulties of considering inoculating this vulnerable population, with the consequent fear of doing more harm to the mother and unborn than good. Because of the inherent challenges to targeting a disease that until recently was seen as rather innocuous, virtually no drug developers have had a background of putting Zika in their crosshairs. And with all the challenges accentuated by this newfound urgency, some outside- the-big-Pharma-box thinking might be necessary.

Vaccines have historically been an area for industry consolidation. “We see pressures where big Pharma has developed epicenters of expertise for vaccine development and manufacturing, said Kevin Fitzpatrick of the IMS Consulting Group. Manufacturing requires massive facilities for growing vaccine products, fill and finish, etc. The safety of

such products that are generally going into healthy subjects, often children, clearly delineates the need for an extreme high bar for safety and quality necessitating top-notch manufacturing. An established reputation for supply security and ability to leverage portfolios commercially-requiring significant up-front investment-have been factors that have made vaccines primarily the realm of big pharma, though certainly exceptions do exist.

That perspective is changing along with the profile of disease. We are seeing more nimble companies who have new vaccine approaches that could offer better, more ready, and proactive approach, explained IMS’s Nitin Mohan. Some of these small companies could capitalize on new technologies for better responses to massive, constant or recurring threats, like the flu, but their platforms may also be valuable in approaching pop-up threats like Zika.

“We’ve made a vaccine construct based on the consensus antigen for targeting the Zika virus, and we think in principle, our approach could do well in vaccinating against the disease,” said Wouter Latour CEO of Vaxart, a South San Francisco-based biotech firm focused on developing recombinant vaccines administered by tablet rather than by injection. Vaxart’s current pipeline is centered on flu, norovirus, and respiratory syncytial virus (RSV), but Latour believes the company’s oral vaccine platform is highly suitable to take on Zika. 

Indeed, the potential benefits of pill-based vaccines are clear for the poorer nations of the world and tropical regions, said Mohan. Vaxart’s technology has some obvious advantages over injectables, being easy to transport and are stable without cold chain storage, which could be essential in outbreaks. Given that a pill doesn’t need to be injected also takes out the need for a healthcare professional to be present when the vaccine is administered, another major benefit in regions with little public health infrastructure. 

Incentives right for small firms

Another biotech firm with a California startup address that thinks it can leverage its expertise is Redwood City-headquartered PaxVax. “Along with many others, PaxVax is now in the early stages for developing a Zika vaccine,” according to CEO Nima Farzan. 

The company has worked on dengue and has proprietary technology targeting that virus, which Farzan thinks could also be applied to Zika. The company hopes to take its early findings into animal tests soon, he stated. PaxVax’s business model emphasizes the pursuit of socially responsible strategies to address unmet medical need while finding a profit by serving the affluent  traveler’s vaccine market. This will give it both the tools and resources to positively  impact the spread of infectious diseases of the developing world.

Zika’s impact on the Brazilian healthcare system and tourism during the Rio Olympiad will certainly be significant. But could there be a dampening effect on attention in the all-important US market, which remains the source for much of the research-and funding-on infectious diseases. Given the uncertainty around the virus’ link to the congenic defect, it is possible that microcephaly will become diminished as a part of the story if a solid link isn’t found. Additionally, with non-vaccine approaches like mosquito control being emphasized, and as summer gives way to winter and the mosquitoes dwindle, calls for a vaccine solution could dwindle, Farzan speculates. Just imagine if the disease fails to cross the borders in sufficient numbers and if the US sees little or no impact. How strong will the resolve be to go forward with an expensive Zika vaccine development program? 

PaxVax’s business model is built to target disease outbreaks in emerging nations, so its incentive structure could keep the firm on track where others might put it on the backburner, should  Zika’s popular prominence lessen. The company’s US-marketed product, Vivotif, an orally administered, live-attenuated typhoid fever vaccine, illustrates its designs around infectious diseases typically non-endemic to the US or other developed regions, which are rarely the subject of conversation or  major headlines.

Another example of PaxVax’s approach is its single-dose oral cholera vaccine Vaxchora, for which it has an action date for approval with the FDA on June 15. The firm has attracted investors, raising a solid $105 million, which it announced in December would go in part to support the launch. PaxVax also hopes the vaccine will warrant a priority review voucher (PRV) from the FDA, a designation that has become an increasingly valuable asset in the industry.

There are existing vaccines available in Europe and India for cholera, but these products are offered in a two-dose format. PaxVax’s product can be given in a single dose, ideal for travelers and thus a US market, but in addition, the impact of a single dose product for outbreaks and natural disaster settings could be substantial. The company’s model, incentivized partially by FDA’s PRV system for which Farzan says PaxVax is a “poster child,” lays out a clear path from profitable drug and/or vaccine development to impacting populations and emerging nations positively. “This is a good example of the PRV system working,” said Farzan. PaxVax’s approach with the PRV incentive in mind proved a major motivator for the company, he said. 

Of note, PaxVax’s clinical testing in cholera included a challenge study in which 120 subjects were given the disease and monitored at US university medical centers. The challenge testing was necessary to show the vaccine’s efficacy in a population that is generations removed from cholera’s ills and thus would never have been exposed to the sickness. Giving 120 volunteers a dose containing cholera is, on the surface, a rather risky strategy, with potential for extremely negative headlines and liability fallouts. It only stands to reason that a big Pharma firm, with huge assets at stake, would feel averse to the consequences. 

Zika could also be an area for aggressive clinical development. And it’s not just Zika. Given globalization, expanding world travel and global warming, the potential for outbreaks is constantly expanding. PaxVax believes small companies with proper incentives may have the mindset to take on risks where others can’t.

Influenza: Bigger incentives

Incentives to develop improved vaccine treatments for influenza are more obvious for big and small vaccine makers, given the diseases seasonal impact in the massive markets of the developed world, not to mention its economic impact with missed work days and ER visits. The disease also remains lethal in vulnerable populations like the elderly. Sanofi Pasteur’s strategy to protect its Fluzone franchise through life cycle management, along with efforts to develop an offering with more broad protection, makes influenza seem like the realm of industry giants only.

But new approaches and the need for faster, more reactive manufacturing processes have innovators making waves. BiondVax Pharmaceuticals, another small vaccine developer, with its sights set on a universal flu candidate M-001, can manufacture its product in six to eight weeks, with the recombinant product fermenting in E. coli overnight. BiondVax has government support and hopes to overcome the challenges in the current flu vaccine set up of requiring vaccination yearly.

Vaxart’s oral approach, targeting the gut immune system, and delivering via a convenient room temperature-stable tablet, has displayed promising results so far. Moreover, where existing vaccines have stumbled to predict and protect, leading to bad flu years, Vaxart thinks it can be more reactive and better prepared with a model protecting against different flu subtypes. Rather than attempting to prognosticate the prominent strains and manufacture doses months ahead of time, Vaxart’s pills could be manufactured closer to flu season and the appropriate pill cocktail can be distributed based on a given year’s predominant strains. 

Vaxart began enrollment of a Phase I trial testing its influenza B tablet vaccine in December. This trial builds on momentum from its earlier Phase I look at its influenza A treatment, which displayed cellular and mucosal response on top of the standard outcome, hemagglutinin inhibition.

Vaxart’s lead programs are targeting norovirus and RSV, for which its tablet vaccines and broad immune responses would offer important potential advantages. The company is on track to initiate Phase I clinical studies for both indications by the middle of 2016. 

A company with building excitement for a RSV vaccine candidate is Novavax, which was the first to ever demonstrate efficacy in any clinical trial in any population for the disease. The company’s senior vice president of research and development, Gregory Glenn, MD, noted that its recombinant protein nanoparticle is grown using insect cell lines, which fold and modify the RSV F protein in unique way. The technology may enable priming of the immune system to create the first vaccine for RSV after over 50 years of failure.

The appetite for a solution in RSV, which strikes infants and elderly, was made abundantly clear when Novavax announced that it had completed enrollment of 11,850 older adults at 60 US sites in December for its Resolve trial, after just five weeks. The company expects top-line results from Resolve in the second half of 2016. Novavax also initiated a Phase III trial, the Prepare study, that will enroll over 5,000 pregnant women. It will  take two to four years to complete. Enrolling healthy pregnant women with much tighter criteria will be a different task than targeting an essentially “all comers” population of elderly trial subjects.

The next wave: Therapeutics

Perhaps the most exciting-and medically revolutionary-work on vaccine is on the therapeutic side for chronic, non-infectious conditions. Vaccines have a sordid history in oncology, but new and improving understanding of the immune system may help overcome past failures. 

Innovative methods for stimulating an immune response means that oncology is seeing an upsurge in interest in vaccine technologies that carry significant  potential.

One company, Neon Therapeutics, launched with a $55 million Series A in October and an impressive list of founders including Eric Lander Jim Allison, Ton Schumacher, and Bob Schreiber. Neon will build its treatments around the new biology of neoantigens.

Cary Pfeffer of Third Rock Ventures, Neon’s interim CEO, explained that ongoing developments in immune oncology like checkpoint inhibitors have broken open the neoantigen space. Novel antigens that arise due to accumulating mutations in tumors are inherently non-self inducing and would be expected to be highly immunogenic. 

Neon plans to develop treatments highly specific to individual patients, as well as vaccines that would target neoantigens shared by patients with similar cancer types. The company intends to file an investigational new drug applications (IND) to start a trial by the third quarter of this year. Along with its support and impressive pedigree of scientific minds, Neon has inked a collaboration with Bristol-Myers Squibb to combine its vaccine technology with the PD-1 checkpoint inhibitor Opdivo in a Phase I look at melanoma, smoking-associated non-small cell lung cancer, and bladder cancer.  

No respect?

While personalized cancer vaccines aren’t likely to carry small price tags, the value of potential cancer cures will be seen as worth the effort. The current Obama Administration “cancer moonshot” strategy for fast tracking these solutions display the popular desire to accept the risks and make the effort. Likewise, vaccines for infectious diseases are already seen as highly cost-effective in terms of overall  population health, though they do not always get the political credit they deserve. 

Given the social consensus around vaccines’ return on investment, greater recognition is due whether it is for the prevention of persistent, nagging diseases that afflict the many but make few headlines or for the sudden outbreaks of smaller, episodic infections that dominate the headlines by terrifying the public. 

The public health payoff from investment in vaccines stands in stark contrast to that of the industry’s modest expectations in terms of profit and earnings, which is why vaccines seldom get top billing as the fodder for conversation in investment circles. But small vaccine developers with biotech-like disruptive technologies are garnering respect on the investment circuit and hoping for significant gains in the clinic. Watch this space-carefully.

Casey McDonald is Pharm Exec’s Senior Editor. He can be reached at cmcdonald@advanstar.com