After completing medical school in the early 1970s, Rolf Zinkernagel hoped to land a position as a hospital physician in sub-Saharan Africa – but his applications to the World Health Organization (WHO) and other international health agencies were rejected.
Instead, Dr. Zinkernagel continued his studies in Switzerland and later Australia, at the John Curtin School of Medical Research, where he and lab partner Peter Doherty made landmark discoveries about the human immune system that earned them the 1996 Nobel Prize in Medicine.
Now, three decades later, Dr. Zinkernagel will get an opportunity to help improve healthcare in Africa as a senior advisor to the Novartis Vaccines Institute for Global Health (NVGH). The new institute is the first established by a major vaccine manufacturer with a nonprofit mission – to discover and develop vaccines for “neglected” diseases of the developing world.
Research activities at NVGH are part of the overarching Corporate Research organization at Novartis and the institute will also leverage scientific expertise and technology platforms at the Novartis Vaccines and Diagnostics Division. Projects at NVGH will be managed separately from the commercial research activities, however. And all vaccines developed by the institute will be provided at an affordable and accessible price to populations of developing countries.
“NVGH is part of Novartis and I’m certainly engaged in Novartis,” says Dr. Zinkernagel who has been a member of the Novartis Board of Directors since 1999. “It will be a real challenge -- these diseases are neglected because making vaccines against them is difficult. But this is also an opportunity to try new things – combining expert science and the know-how of a company with a proven track record of translating ideas into concrete products.”
Corporate Citizenship
NVGH is the latest initiative reflecting a far-reaching commitment to Corporate Citizenship by Novartis. Thanks to its commercial success, Novartis is able to make investments that improve access to medicines and vaccines for poor patients in the developing world who otherwise could not afford them. During 2007, treatments worth USD 937 million were contributed through access-to-medicine programs at Novartis, reaching more than 66 million patients in need.
“For commercial reasons, major pharmaceutical companies traditionally devoted little, if any, research activities to major diseases that occur predominantly in the poor parts of the world,” says Professor Paul Herrling, Head of Corporate Research at Novartis. “That has changed in recent years and Novartis has allocated some of our research and development skills and technologies to address neglected diseases, from tuberculosis (TB) and dengue fever to malaria. We also have introduced initiatives to train students from developing countries in the skills needed to translate basic science into medicines.”
The mission of NVGH mirrors the Singapore-based Novartis Institute for Tropical Diseases (NITD) that was established in 2003. Both institutes focus on research and early stages of development, to the point of proof-of-concept in man. Medicines or vaccines discovered by the institutes will be made available to endemic countries at no profit.
For late-stage development -- and even production, in the case of vaccines -- Novartis plans to work together with financial and operational partners. Under the leadership of Dr. Herrling, Novartis is playing a pioneering role within the pharmaceutical industry in forging novel partnerships with non-governmental organizations, charities, academic groups and government agencies.
Of course, some of the institutes’ most important partnerships are with scientists across the Novartis commercial research network. “Novartis researchers around the world are extremely motivated to use their science to make contributions to access to medicine,” Dr. Herrling adds. “Without their help, our not-for-profit institutes wouldn’t be as effective.”
Scientific luminaries like Dr. Zinkernagel and other members of the NVGH scientific advisory board are another prized resource. Yet the advisory board also includes members such as Sir Gustav Nossal and Ciro de Quadros who helped shape policy and broaden use of vaccines in recent decades, saving millions of lives in the process, through senior roles at international organizations such as the former Children’s Vaccine Initiative, the Global Alliance for Vaccines and Immunization (GAVI) and the Pan American Health Organization (PAHO). Their experience and advocacy will help ensure that vaccines from NVGH actually reach the people who need them most.
“There is nothing more frustrating than having new drugs and vaccines available but not actually reaching patients and people who need them,” Dr. Herrling says. “We experienced that with our breakthrough antimalarial drug Coartem, a medicine that works with more than 95% efficacy against all the strains of resistant malaria parasites we know of. But it took years to convince governments, societies and patients that needed Coartem to use it,” he adds. “So we realized that we need to be aware of policy issues and begin to make contacts with key stakeholders even before the NVGH labs started working.”
Making a difference
Novartis inherited the idea of a not-for-profit vaccine research through its acquisition of Chiron Corp. in April 2006. Rino Rappuoli, Chiron’s Chief Scientific Officer and head of vaccines research, had dreamed for decades of applying the same sophisticated technology and passion he invested in commercial research to develop vaccines for the developing world.
“Vaccines are powerful and you knew you could really make a difference,” Dr. Rappuoli says. “But because of the way companies are organized, we always ended up developing commercially viable vaccines, which meant ones that were needed in Europe and the US.”
In the early 1990s, Dr. Rappuoli developed a vaccine against two strains of Neisseria meningitis, the bacterium that causes most cases of meningococcal meningitis. The Men A strain of N. meningitis causes major epidemics in Africa while the Men C strain was needed for protection in Europe and the US. Clinical trials of the combined Men AC vaccine were progressing well, Dr. Rappuoli recalls, when prospective customers including the UK government asked that the African component be removed from the vaccine. Chiron complied -- and the Men C vaccine was eventually approved and launched in the year 2000.
“It was a clear example where not only the company but European countries were against developing a vaccine that was needed in developing counties,” Dr. Rappuoli sighs. “I’ve seen this many times.”
Eventually, he began to explore the possibility of establishing a separate non-profit foundation to develop vaccines for the developing world. Plans for such a foundation were well advanced by the time Novartis bought Chiron.
After the acquisition, Dr. Rappuoli agreed to remain head of research at the new Novartis Vaccines Division. And he reviewed his plan for a neglected disease research institute during an early meeting with Joerg Reinhardt, Head of the Vaccines and Diagnostics Division. Dr. Reinhardt supported the plan, as did Novartis Chairman and Chief Executive Officer Daniel Vasella at a later meeting with Dr. Rappuoli.
Dr. Vasella vetoed the idea of a separate foundation, however, preferring to model a vaccine institute on NITD. He also asked Dr. Rappuoli to convene a meeting of key stakeholders to review the proposal and, after a ringing endorsement of the plan by major stakeholders, the Novartis board of directors subsequently approved creation of the new institute.
Top priority – diarrheal diseases
In September 2007, Allan Saul was appointed Chief Executive Officer of NVGH. A native of Australia, Dr. Saul had spent more than 20 years in vaccine research, most recently with a malaria vaccine development unit at the US National Institutes of Health. His career also included extensive fieldwork in countries ranging from the Philippines and New Guinea to Mali and other parts of Africa. “I’ve been exposed to many of the disease problems that occur in developing countries and that also has brought me a lot of contacts with people who work with vaccines in the field,” Dr. Saul says.
One of his first steps at the new institute was to compile a list of diseases of significance in the developing world – ranked according to total disease burden as well as whether a vaccine could significantly reduce that burden and be delivered within a few years. The initial list of 57 diseases was reduced to 22 candidates – of which 17 are of potential interest but need more basic research or have a longer time frame for vaccine development, Dr. Saul says.
The remaining five priority targets are diarrheal diseases that take a daunting toll among children across the developing world. According to the WHO and the United Nations Children’s Fund (UNICEF), an estimated four billion cases of diarrhea occur worldwide ever year, resulting in more than 2 million deaths, mostly among children under the age of five in developing countries. “In fact, diarrheal diseases cause the vast majority of clinically important disease in the world,” Dr. Saul adds.
While major infectious diseases like HIV/AIDS or tuberculosis are caused by a single organism, multiple different pathogens are responsible for diarrheal diseases. The first projects selected by NVGH are vaccines against infections caused by Salmonella bacteria. Salmonella typhi – the bacterium that causes typhoid fever -- has largely disappeared from the West but it is still a major public health problem in the developing world, causing an estimated 22 million cases and at least 200 000 deaths annually. There are two existing vaccines for S. typhi but neither works in young children, who constitute a sizable proportion of the incidence of disease victims. Moreover, because S. typhi can only infect humans, these young children also represent a major reservoir of infection. “We really need vaccine against S. typhi for these young children,” Dr. Saul says.
A second bacterium, Salmonella serotype paratyphi A, causes paratyphoid fever, long considered a “poor cousin” to typhoid fever . More than 5 million people are infected every year and in several parts of the world, including China, paratyphoid fever has emerged as an important disease.
The third form of salmonella of interest to NVGH is non-typhoid Salmonella bacteria (NTS). Many different strains of NTS have been identified. In industrialized countries they cause gastroenteritis infections from eating contaminated food but in sub-Saharan Africa, NTS is a major killer. Exact epidemiological data aren’t available for the entire continent but in countries such as Kenya and Malawi, NTS is a leading cause of hospital admissions for children and ranks among the top three causes of death among children under five years of age.
Speaking at the inauguration of NVGH in February, Samuel Kariuki of the Kenya Medical Research Institute called NTS “an epidemic and a public health emergency, but one that still isn’t widely recognized outside of sub-Saharan Africa.” According to Dr. Kariuki, NTS afflicts adults in Africa as well, particularly people already infected by HIV, ranking in importance after pneumococcal pneumonia and tuberculosis. Recurrent NTS infections are increasingly common among HIV-positive individuals, producing mortality rates approaching 50%.
Adding to concern, a large proportion of NTS strains have developed resistance to the antibiotics traditionally used to fight infections. “The cheap drugs don’t work any more because of resistance – in some places we are finding that up to 50% to 60% of isolates are multi-drug resistant,” Dr. Kariuki adds.
The two remaining priority projects at NVGH are vaccines against strains of the Shigella bacterium and Enterotoxigenic Escherichia coli (ETEC), Shigella is another major killer, accounting for an estimated 160 million infections and 1.1 million deaths in the developing world, the majority children under five. ETEC causes more than 200 million diarrheal episodes and an estimated 380 000 deaths annually.
“A good match.”
Dr. Saul emphasizes that programs at NVGH will be highly collaborative. “We will be heavily involved with groups in academia and research institutes. For most of the diseases we are looking at there already are people out there who have identified candidate antigens and are trying to find industrial partners that would help make vaccines. It’s actually a good match,” he adds.
“The big gap in vaccine development is taking that idea from the laboratory through proof-of -concept in humans – that’s where we see the primary role of NVGH,” Dr. Saul says. “But to take these vaccines through the development process, we’ll also need field collaborators. There are field sites that we can build on – even if some of them need to be strengthened further. The problem at the moment is that these field sites don’t have vaccines to test.”
Ogobara Doumbo, a physician affiliated with the Malaria Research and Training Center of the University of Bamako, Mali, welcomes the commitment to training by the NVGH as a way to accelerate development of new vaccines – and also reverse the brain drain of healthcare professionals from Africa. “We need more innovative ways to increase the proportion of trained people who stay and work in endemic countries,” Dr. Doumbo says.
One such novel approach is a collaboration between NITD, the University of Basel and the University of Singapore and the Swiss Tropical Institute offering a Masters degree program. Students spend half the year in Basel and the remainder in Singapore and in addition to work in the classroom and lab, they receive broad experience in clinical fieldwork. Successful graduates get a double diploma from both universities so that they can start their careers either in Europe or Asia, Dr. Herrling says.
To commemorate the inauguration of NVGH, the institute has funded a fellowship for a program run by the institute in conjunction with the Swiss Tropical Institute, leading to a Masters degree in Infectious Biology and Epidemiology. “This inauguration fellowship is an investment in human resources instead of a plaque to hang on a wall,” Dr. Saul said. “We hope that this will be part of a broader program at NVGH -- looking at the way in which vaccines interact within the health service – that can be of use to healthcare systems in the developing world.”
Manufacturing is another key link in the supply chain where Novartis plans to recruit partners. “We shouldn’t rule out Novartis being a manufacturer but I think we’ll probably need a range of manufacturers for our vaccines,” Dr. Saul says. In the vaccine business, however, commitments by manufacturers usually are necessary before starting the pivotal round of clinical trials. “The challenge will be to take a project far enough to make a prospective manufacturer confident enough to pick it up and run with it,” he adds.
Meanwhile, NVGH will be building links with health agencies and governments to help with delivery of vaccines. “We’re still only a very young organization and over the next few months one of our big priorities will be putting in place networks of field workers while also starting to look at manufacturers and to talk with regulatory authorities,” Dr. Saul says.
Portfolio management
NITD, the Singapore-based institute faced similar challenges in recruiting partners to help finance late-stage development of drugs it discovers. Significant progress has been achieved in recent years, however, and commitments are now in place for all three priority disease areas – malaria, tuberculosis and dengue fever.
In 2006, NITD agreed to expand into malaria research under a five year, USD 20 million collaboration funded by the Wellcome Trust, Medicines for Malaria Venture (MMV) and the Singapore Economic Development Board. “The Wellcome Trust and MMV have asked us to start a new program to find the next generation of malaria compounds after artemisinin-based combination therapy, the category pioneered by Coartem,” Dr. Herrling says.
Meanwhile, the Global Alliance for TB Drug Development has agreed to co-finance late-stage development of compounds discovered by NITD for treatment of drug-resistant TB. NITD and the Wellcome Trust are also at an advanced stage of negotiations about an agreement to provide financing for late-stage development of medicines from NITD against dengue fever.
Moreover, Dr. Herrling is playing a leading role in an intra-industry initiative to establish a fund to provide additional financial resources to stimulate research and development into neglected diseases. Reflecting a commitment by Novartis and several other major companies to support research targeting neglected diseases in the developing world, an emerging portfolio of almost 90 new medicines is against neglected tropical diseases and TB is advancing toward clinical trials drugs – and will require billions of dollars in additional funding to complete development.
“A lot of these projects will fail in clinical testing but even if 10 projects make it through development we can’t afford to develop all of them with the money available today,” Dr. Herrling says. “It would be tragic to have development of viable medicines stop after Phase II, with both drug discovery completed and positive proof-of-concept in man after Phase II.”
The proposed fund would borrow portfolio management model applied in industry, an area of acknowledged expertise. “You don’t want to give huge lump-sums of money – in a project you provide enough funding to reach the next transition point in testing,” Dr. Herrling adds. “Depending on the trial data, you can continue to invest or stop the project.”
The fund would have a board with representatives from governments, donors and so on who would make strategic decisions like which diseases to focus on. “But technical decisions on individual projects would be delegated to a group of technical experts, experienced pharmaceutical executives,” he adds.
In return for financing, the Fund would receive an exclusive license from the financed indication and would guarantee that if development was successful, the medicine would be made available at cost to endemic countries. Still, originator companies would retain intellectual property rights to any additional commercial indications for the same compound.
“The idea has broad support within the industry so far,” Dr. Herrling says. “The next step is to see if we can put together something that even groups like Medecins Sans Frontieres or Oxfam agree we should try. And we need to see if at least a few governments will be prepared to buy in. If it’s done rationally – with a strong commitment from industry – it should generate confidence that it can really produce new medicines against these neglected diseases.”
Eliminating unnecessary human suffering
Ciro de Quadros, a member of the NVGH scientific advisory board, began his medical career doing fieldwork in a small clinic in the Amazon rainforest of his native Brazil. Later, Dr. de Quadros joined the WHO smallpox eradication program in Ethiopia and then returned to the Americas to lead the landmark Expanded Program on Immunization (EPI) for PAHO. He led the PAHO team in the successful regional eradication of first smallpox, and later polio and measles.
Writing in the American Journal of Public Health in 2004, he predicted that enormous progress in research and development “encourages us to believe that this century will be the Century of Vaccines.” Dr. de Quadros cautioned, however, that it is incumbent on governments to ensure that resources will be available for the early introduction of the new vaccines that represent “the most certain way to eradicate other vaccine-preventable diseases and eliminate unnecessary human suffering.”
That remains a formidable challenge. A series of international initiatives helped make immunization programs targeting children and women of childbearing age one of the most successful and cost-effective public health interventions in history. Between 1980 and 1990, worldwide immunization with DPT3 vaccine, a proxy for overall immunization coverage and child health, climbed to 75% from 20%, according to the WHO and UNICEF.
Other important vaccines such as Hepatitis B remained underutilized, however. The creation of the Global Alliance for Vaccines and Immunization (GAVI), with financial backing from the Bill and Melinda Gates Foundation as well as government donors, helped to double the number of countries offering Hepatitis B vaccination between 1997 and 2004. Yet the WHO and UNICEF estimate that 27 million infants and 40 million pregnant women around the world were not immunized in 2003 and about 2.5 million children under five years of age still die every year as a result of diseases that can be prevented by vaccination, using currently available or new vaccines.
Clearly, the flood of new vaccines foreseen by Dr. de Quadros and other public health leaders would increase the cost of global vaccination programs. The annual cost of supporting routine immunization and introducing new vaccines in least-developed as well as low- and middle-income countries will rise to USD 6 billion by 2015, triple the estimated USD 2 billion spent during 2005, according to a study sponsored by the Albert Sabin Vaccine Institute two years ago.
“Powerful economic rationale”
To bridge that gap, governments and major donors have introduced innovative funding mechanisms in recent years. Political commitments from some of the world’s wealthiest countries have pushed healthcare higher on the development aid agenda – and as the most cost-effective healthcare intervention, vaccines exert a powerful appeal for Finance Ministers charged to ensure that public money is spent prudently.
“That old saying ‘Prevention is better than cure’ isn’t just common sense – it’s a very powerful economic rationale,” says Carlo Monticelli, an official from Italy’s Ministry of Finance, who spoke at the NVGH inauguration.
Nonetheless, Mr. Monticelli admitted that global resources devoted to finding new vaccines are still far below the social optimum. “Some economists and policymakers tell you that the market should take care of this – but that hasn’t worked in the case of vaccines,” he mused. “In fact, it’s a textbook example of market failure.”
Remedial measures have been undertaken at the highest levels – including the Group of Eight (G-8), the world’s eight most industrialized nations that meet regularly to discuss and draw up global economic policies. Initiatives such as Advance Market Commitment (AMC) and International Financing Facility for Immunization (IFFIm) have made billions of dollars available to support research or finance vaccine purchases by poor countries.
Advance Market Commitment is a model aiming to spur development of vaccines against diseases prevalent in the developing world. A pilot program targeting pneumococcal disease, a major cause of pneumonia and meningitis that kill more than a million children every year, has received funding commitments of USD 1.5 billion from Italy, the UK, Canada, Russia and Norway – plus the Gates Foundation.
The AMC model uses public money to create a market that otherwise wouldn’t exist. Sponsors make a legally binding commitment to pay an agreed price for a vaccine – on condition that the vaccine meets pre-agreed criteria and developing countries want to use it. Mr. Monticelli insists that by contrast to direct funding of research “that boils down to a bureaucrat choosing a particular avenue of research as opposed to another,” the AMC model leaves pharmaceutical companies free to choose the avenues of research that they consider most promising.
At the same time, money is spent against results and only paid out against delivery to countries that will use the new vaccine, a key consideration for Finance Ministers and taxpayers, he added. Underscoring the appeal of the AMC model, it took a mere two years from the initial presentation by Italy at a G-8 meeting in February 2005 to unanimous approval by G-8 Finance Ministers and launch of the AMC pilot program in February 2007.
Separately, IFFIm is a program originally proposed by the UK government that uses pledges of future grant funding to raise money from international capital markets for immediate use. Specifically, pledges by donors are used to issue triple-A rated bonds and proceeds from the bond issues are channeled by GAVI into vaccination programs. Bonds are eventually redeemed when funds are actually disbursed by donors.
The initial IFFIm bond issue in November 2006 raised USD 1 billion, based on pledges from the UK, Italy, France, Spain, Sweden and Norway. Over the next decade, IFFIm is expected to raise a total of USD 4 billion from existing and new sponsors, such as South Africa and Brazil. That investment is expected to prevent deaths of more than 5 million children and an equal number of adults between 2006 and 2015.
An early look ahead
When Dr. de Quadros was invited by Novartis to an international conference in Siena, Italy last summer to discuss plans for NVGH, he quickly became convinced that the institute was a timely initiative that could make crucial contributions in improving access to vaccines in the developing world. “There is a whole array of things that needs to be tackled,” he adds. “What’s the most cost-effective way to deliver a product; how much can NVGH contribute in terms of looking at the installed capacity for diagnostics, and for disease surveillance. This idea of training is also brilliant – to have younger people being trained at the lab bench as well as doing studies in the field and looking at community acceptance. It’s fundamental. And it’s very encouraging to see that NVGH is looking at these downstream aspects of vaccine research and development at such an early stage of operations,” he adds.
“This is something that will give added visibility to the field of neglected diseases,” he says with a smile. “The idea has been very well received by people I talk to in Washington D.C. and other world capitals. In fact, many have even begun to ask why it took so long for someone to finally decide to do it.”
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