Research labs across the world are pouring money into finding a viable vaccine for the Ebola virus. A small start up nestled in Delhi’s Jamia Hamdard University is also thinking big: adding value to existing vaccines by making them more effective for populations in developing countries By Shalini Gupta
The recent outbreak of Ebola virus disease (Ebola) has brought to the fore the importance of vaccines as a tool for public health as companies are gearing up to be the first in line. However, unlike drugs, developing a vaccine is not easy. While the search for vaccines begun with diseases such as smallpox, cholera, rabies, measles etc, today the unmet needs lies in having vaccines against malaria, herpes, flu and even for diabetes and cancer. Yet, despite the huge public health impact that they create, they present both a tremendous opportunity and a challenge. In an important development, Novartis recently sold off its vaccines division to GSK, with a long standing expertise in the area.
Collaboration is the word
What is needed today is not only the development of novel vaccines, but optimising existing vaccines to better suit the needs of populations across the globe and this is where Delhi-based Hilleman Labs comes across as an interesting example of venturing into formidable territory with a strategy few can match. In 2006, two oral vaccines, Rotarix by GlaxoSmithKline and RotaTeq by Merck, both against Rotavirus infection A were shown to be safe and effective in children. They contained genetically engineered live attenuated human rotavirus strains or hybrid human-bovine re-assortment rotavirus strains. Three years later in 2009, WHO placed rotavirus on its list of critical immunisations for all its national programmes.
Taking cognisance of these developments, the same year saw the inception of Hilleman Labs, an R&D joint venture set up by the Wellcome Trust and Merck with a not-for-profit mission to focus on developing affordable vaccines to prevent diseases that commonly affect low-income countries. Fast forward to 2014 and in July this year, Prime Minister Narendra Modi added four new vaccines to India’s Universal Immunisation Programme (UIP) including rotavirus (rubella, injectable polio and Japanese encephalitis) which further underscores the importance of the path Hilleman has committed itself to.
Today this small start up company with a staff of less than 50 people has a pipeline of two prominent vaccines, one for rotavirus and the other for cholera. Both the vaccines are in the pre-clinical stage, undergoing toxicology studies which will finish by the end of this year. There is still a long way to go, and Hilleman Labs is not one to take short cuts. Traditional pharma models have a bench to bedside approach negating any outside influence, implying they shoulder all the risk of developing the product and taking it to market. However, Hilleman Lab’s approach is different.
“The pharma model says, we know what the problem is, we know how to solve it and we can fix it ourselves. There is this inherent notion that the entire spectrum of the solution resides within the organisation and hence by virtue of that the burden of risk is huge. We are promoting a collaborative model. Even as we bring a unique perspective to the vaccine space, we realise that we don’t have the expertise for the entire spectrum and so we need collaboration. Together we are more likely to solve the problem than by doing it ourselves and attract funding and support. Secondly by doing this, we are reducing the risk since we have other partners who have the expertise,” elaborates Dr Davinder Gill, Chief Executive Officer, Hilleman Labs.
He took over in January 2012, when there was a shuffle in the management and helped formulate a roadmap and vision. With an experience of close to 15 years in the pharma industry ranging from start ups with as less as 15 people to multinational companies, he has seen the innovation, rigour and skill required for R&D and drug development from close quarters. He was also involved in setting up R&D facilities for Hilleman Labs in Europe, namely Ireland and Scotland, working with the local government. However, a lot of foresight has gone into setting up the India operations and it wouldn’t be incorrect to say that it has rightly put its money where its mouth is. “Unlike Biotechs which don’t hesitate to put their money behind a crazy idea, our concept was that we would not begin on a project unless we had a clear line of sight on its public health impact as well as utility to a larger population,” he chips in.
David Vs Goliath?
Unlike drugs where even small companies are manufacturing niche therapies, vaccine companies have traditionally been into the business and are huge. GSK, Merck and Sanofi to name a few. So is Hilleman Labs trying to take on these Goliaths? The answer is no. It is not trying to fulfill a significant unmet need, in say, malaria, HIV, tuberculosis, or dengue and try to come up with something novel, but rather optimising existing vaccines, rotavirus (for thermo-stability) and cholera (making it more affordable). It is about combining the manufacturing aspect with the thermostability aspect. It hopes to achieve a proof of concept in the next five years as the candidates enter the orbit of advanced clinical development soon.
Having chosen such a goal, getting there must be fraught with challenges especially in the Indian ecosystem with a resource crunch and inadequate infrastructure even as one has to carry out cutting edge R&D of global standards. This is where a focused approach and SWAT anaylsis comes in. A biotech company in India usually begins with an idea that originates at an academic lab somewhere and the company is put together. It was the other way round for Hilleman Labs, it was decided that it would focus exclusively on translational R&D in the vaccine space. Rather than taking up complex diseases such as HIV, malaria, TB, where the likelihood of success over a period of say 10 years is small, it took over the mantle of putting a twist to existing vaccines.
“Working in a tiered approach, we broke down our future in five year cycles and decided that right at the outset, lets take those products that do exist, but they aren’t necessarily designed or optimised for the use of the developing world. By doing so, we’d have established ourselves by building capacity and capability. In the next five-year cycle, we could envision taking up new things, that don’t exist, that includes novel vaccines,” echoes Gill. Zeroing upon this approach took time, picking and choosing the right targets, but it is more practical and is being executed to a T right now. “We looked at mortality data for infants less than one year of age for countries like India and found that they either have severe respiratory or gastrointestinal infections. Thats where we decided on enteric diarrhoeal disease as an area to focus on so that is where rotavirus, cholera and some of the other things fit in,” he adds.
The biggest risk in vaccine R&D is technical- will the innovative idea on paper ever become a product or not. With reference to thermostable vaccines, there were two schools of thought. One is that we need thermostable vaccines and other asks why? Partnership was crucial to scale up this innovative approach. Hilleman Labs understood early on that it doesn’t have all the pieces of the puzzle and its absolutely fine to be in that spot. It partnered with Gotovax AB, a biopharmaceutical company, spun off from the University of Gothenburg, early this year for its cholera vaccine.
The company today is an amalgamation of these three strategies: a tiered approach, focus on enteric diarrhoeal diseases and the partnership model which not only helps it leverage its resources but also reduce risk. It has been able to crack that strategy and able to demonstrate technical excellence with both the programmes in pipeline. Partnership for manufacturing and commercialisation is crucial and it has already begun talks with manufacturers within and outside India to see these projects through to commercialisation through both national level and procurement agencies.
Miles to go before hitting the market
20 years back a set of guidelines from WHO were available to countries for expanded immunisation programmes. It was when agencies like The Global Alliance for Vaccines and Immunizations (GAVI) stepped in, that vaccination came top on most countries priority list from a public health perspective. The challenges of today are in the implementation looking at the size, scale and heterogenity of the population as well as health, education, sanitation, infrastructure in countries etc. “A country like India is stepping into a Catch 22 situation. While at the national level the government is struggling to see that 95 per cent of the babies born annually get vaccinated, at the grassroot level, vast majority of mothers aren’t aware of the benefit of vaccination,” envisions Gill. However, he is positive that 20 years from now, we shall see more awareness.
As companies come up with newer and innovative vaccines, two factors will be differentiator: affordability and efficacy. “How can one come up with novel processes to make complex vaccines cheaply? Once this question has been addressed, there will be a strong demand for vaccines that are just as effective in low resource countries as they are in developed countries,” he feels. The company itself is looking at how oral vaccines can be combined and delivered, be it through innovative delivery systems or reducing dosing regimen, maximising the impact of multiple vaccines using the most efficient delivery mechanisms. However, this might not always be possible, since not all pathogens affect us at the same time in our lives. For e.g. India has a lot of rabies vaccines, used sparingly due to an eight dose regimen which is difficult to adhere to. The holy grail is a one dose vaccine, however, considering how the immune system works, it remains to be seen how that can be a reality.
Cold chain storage and distribution presents another formidable challenge. It takes approximately a year for a product to reach a primary healthcare centre when it starts out from a government medical store. This creates a forever increasing burden, as the birth cohort increases and more vaccines are added to the system. Having a thermostable vaccine which can survive at 45 degree celsius for a year and bypass the system, such as Hilleman Lab’s rotavirus vaccine could have a profound impact. As per projections by UNICEF, by 2016, 180 million doses of rotavirus vaccine will be required just for the GAVI public market. Adding the GAVI private market and India to this would total 250-300 million doses per year. The company hopes to create a dramatic impact even if it is able to cater to one fifth of this market to begin with.
With India topping the list of developing countries including Indonesia, Pakistan and Nigeria when it comes to rotavirus infections, the opportunity is huge. Sub-Saharan Africa, South-east Asia, Bangladesh and China are other promising markets. With notable rotavirus vaccines already in the market, how important then is it to be first to market? Gill feels that unlike drugs, in the vaccine business, the first in class, is not necessarily the best in class. “I’d strongly argue that for the developing world the product that is actually going to win in the end is the best in class. That means a product which is safe, affordable and ranks good in field adaptabilty,” he exhorts.
Hilleman Labs is surely a company to watch out for in the coming years. It has set up an ambitious target for itself and is galloping fast towards its goal. However is in no hurry to reach there, lest there be any compromises. Gill is hopeful that the clinical trial scenario in India is on the brink of a change and this should bode well for the company whose products are soon to reach that stage. “In the next stage, we are looking at successful completion of our programmes as well as incorporating new ideas into our R&D portfolio. Through a combination of those, we aim to achieve our operating goals to make ourselves financially sustainable in the long run while staying a lean and agile biotech company,” he concludes.
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