New medicines for neglected diseases
Vaccines for the developing worldThe acquisition by Novartis of Chiron Corporation in April 2006 was the springboard to expand pro bono research to vaccines.
Rino Rappuoli, Chiron’s Chief Scientific Officer and Head of Vaccines Research, had dreamed of channeling the same sophisticated technology and passion devoted to commercial research to vaccines for the developing world. “Vaccines are powerful and I knew we could really make a difference,” Dr. Rappuoli enthuses. “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.”
Agreeing to remain with Novartis and head research at the new Vaccines Division, Dr. Rappuoli won support for a proposed not-for-profit vaccine research initiative from both Dr. Vasella and Joerg Reinhardt, at that time Head of the Vaccines and Diagnostics Division. The proposed creation of a new institute was endorsed at a meeting of key stakeholders and approved by the Novartis Board.
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 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, where he was exposed to many of the disease problems that occur in developing countries and gained understanding of working with vaccines in the field.
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 highest priority projects target diarrheal diseases that take a significant 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 every year, resulting in more than two million deaths, mostly among children under the age of five in developing countries. By contrast to major infectious diseases like HIV/AIDS or tuberculosis that are caused by a single organism, multiple pathogens are responsible for diarrheal diseases.
Diarrheal diseases cause the vast majority of clinically important disease in the world.
The first vaccine projects selected by NVGH aim to protect have been vaccines against infections caused by Salmonella bacteria, a major source of diarrheal disease. Salmonella Typhi, the bacterium that causes typhoid fever, has largely disappeared from developed Western countries but it is still a major public health problem in the developing world, resulting in more than 22 million infections, resulting and an estimated 200 000 deaths every year. 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.
In 2010 – only two years after its formal opening – NVGH initiated clinical testing of its first vaccine, known as Vi-CRM197, against S. Typhi. Such rapid progress builds on prototype vaccines developed by leading academic groups as well as technology provided by the Novartis Vaccines and Diagnostics Division. “This is the first of what we hope will be many examples of what can be achieved by matching the experience and expertise of industry with potentially good solutions to pressing public health problems developed by an academic group,” Dr. Saul says.
Protecting infants and children
During a distinguished career, John B. Robbins, M.D., Head of the Laboratory of Developmental and Molecular Immunity at the US National Institute of Child Health and Human Development, has concentrated on problems of immunity in infants and developed breakthrough vaccines for diseases of infants and children.
The accomplishments of Dr. Robbins and his colleagues include the pioneering discovery that Vi, a polysaccharide found on the capsule of S. Typhi, induces immunity when used as an antigen, or active ingredient in a vaccine. The identification of Vi (the acronym is short for “virulence factor”) led to development of vaccines: most recently, a prototype “conjugate” vaccine in which the Vi antigen is combined with a carrier protein to enhance immune response and broaden effective protection beyond adults and teenagers to include infants under 2years of age.
“We know from published data that the vaccine works in young children and gives long-term protection,” Dr. Saul says. “But despite the promising results from trials done over 10 years ago we still do not have a commercial vaccine that is available for use in the public sector.”
That is a common dilemma for academic researchers, who lack the validated expertise in development and production possessed by companies with longstanding industry experience. As a case in point, the prototype Vi conjugate vaccine developed by the Robbins group left room for improvement. “We took a hard look at each of the steps involved in the process and found that, from a commercial perspective, there were several steps where significant improvements could be made in the manufacturing process,” Dr. Saul said.
For example, the Robbins group used Vi polysaccharide from the so-called Ty2 strain of S. Typhi – a strain so virulent that it can only be worked with in BSL 3 laboratories, the next highest of four levels of bio-containment security. Moreover, like many S. Typhi strains, Ty2 is difficult to cultivate, growing best in an expensive broth of mashed yeast. Unfortunately, that growth medium further complicates purification of Vi in production, involving highly toxic chemicals.
Instead, NVGH developed a method to grow Vi in different bacterium, called Citrobacter, that is safer to handle, requiring the lowest level of bio-containment safety, BSL1. The Citrobacter strain selected by NVGH grows to high cell densities, enhancing productivity compared to use of Ty2.
“We’ve been able to adapt methods originally developed by Novartis Vaccines for purifying polysaccharides from other organisms that completely avoid the need for the nasty chemicals used with Ty2,” Dr. Saul explains. “Overall, our process is cheaper and simpler – and easier to manufacture satisfactorily in developing countries.”
The Novartis Vaccines and Diagnostics Division will support NVGH with supplies of a different carrier protein than the one originally used by the Robbins group. Known as CRM197, the carrier protein is a unique, chemically inactivated variant of the bacterium that causes diphtheria. Dr. Rappuoli did pioneering work on development of CRM197 in the early 1980s and over the next two decades the protein became a vital component in vaccines against the leading causes of bacterial meningitis. CRM197 is a key component of Menveo, the conjugate vaccine from Novartis against four of the five main causes of meningococcal disease.
Novartis is one of a handful of vaccine manufacturers currently able to produce CRM197. “Novartis Vaccines has agreed to provide supplies of CRM197 to meet the needs of vaccines we are developing at a price that would make the vaccines affordable,” Dr. Saul says. “That has opened up a much faster route to develop our Vi-CRM197 vaccine.”
While an improved vaccine against S. Typhi alone would be an important contribution to public health, the Vi-CRM197 vaccine also represents a key component in a vaccine targeting Salmonella serotype Paratyphi A, the bacterium that causes paratyphoid fever. Long considered a “poor cousin” to typhoid fever, paratyphoid fever has emerged as an important disease in its own right. More than five million people are infected every year and the proportion of paratyphoid fever is rising rapidly in proportion to typhoid fever.
“We believe that what is really needed is a vaccine that is going to cover both S. Typhi and Paratyphi A,” Dr. Saul continues. “There is no vaccine anywhere in the world for Paratyphi A. It is completely new territory.”