New medicines for neglected diseases
Robust vaccine formulations
Development of the Vi-CRM197 vaccine mirrors the rapid evolution of NVGH. During 2009, the institute raced to assemble its technical development group responsible for setting up a manufacturing process for its maiden vaccine. This was critical in bringing production of Vi-CRM197 in line with requirements of Good Manufacturing Practices (GMP), the industry standard.
Expertise in technical development is the linchpin of NVGH strategy. In a 2008 letter to the Journal of Infection in Developing Countries, Dr. Saul and Dr. Rappuoli observed that while years of patient research have identified likely candidates for vaccine development, the critical missing link is often the production of pilot scale lots of the candidate vaccine. “This requires production methods to be scaled up; robust formulations to be developed; the vaccines to be produced in GMP conditions and tested for stability; toxicology studies to be performed and regulatory documents to be submitted and finally the vaccine to be tested for safety,” they outlined. “The place where this scarce knowledge is present is in a few large vaccine manufacturers that have the experience to conduct this obscure but essential work.”
As clinical trials of Vi-CRM197 commenced during 2010, the clinical development group has undergone dynamic growth. Many of the medical centers selected to participate in clinical trials also have a high prevalence of paratyphoid fever, meaning that the second part of that bivalent vaccine will slot in more easily than if an entirely new study site had to be found.
The Wellcome Trust, one of the largest medical charities in the world, has awarded NVGH a grant of Euro 5.15 million to fund the bivalent (S. Typhi and Paratyphi A) vaccine project from preclinical development through Phase II studies. Dr. Saul has also forged scientific partnerships with the Wellcome Trust Sanger Institute, a genomic research center located near Cambridge, England, as well as the University of Birmingham (England) for the Paratyphi A project. Financial grants from both the government of Italy’s Regione Toscana and the Fondazione Monte dei Paschi have supported preclinical work on the Vi – CRM197 vaccine.
The “Century of Vaccines”
Strong links with industry and public health authorities offer NVGH valuable insights into the needs of its diverse stakeholders. “You can’t really expect the public health official to understand some of the complexities of vaccine development and production,” Dr. Saul acknowledges. “The experience of Novartis enables us to explain choices that are available – and to recommend which alternative we believe will work best. That’s part of the equation.”
The cost of vaccination, for example, comprises the cost of the vaccine itself but also the cost of delivery. With the Vi-CRM197 vaccine, the institute is trying to design a vaccine that is both affordable to produce and offers economies in delivery. “Part of our rationale in going for a vaccine for 6-week-olds is that it is the age when babies are visiting the clinic anyway to get their regular infant vaccines,” explains Dr. Saul. The alternative would be a school-based campaign, or a stand-alone program in which parents would have to bring children to a clinic for no other reason than vaccinations against S. Typhi. “Either would add considerably to cost,” Saul stresses.
Such a grounded, pragmatic approach is reinforced by the institute’s scientific advisors. Sir Gustav Nossal and Ciro de Quadros – members of the NVGH advisory board – are pivotal figures who have 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.
Dr. de Quadros began his medical career doing fieldwork in a small clinic in the Amazon rainforest of his native Brazil. Later, he 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 – as well as successful regional eradication of 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.” And when Dr. de Quadros was invited by Novartis to an international conference in Siena, Italy, last summer to discuss plans for NVGH, he left 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 need to be tackled,” Dr. de Quadros says. “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.”