Affordable conjugates for typhoid vaccines

A low-cost process for producing the active ingredients in typhoid and paratyphoid vaccines could put a life-saving joint vaccine within the reach of developing countries.

Typhoid infects over 20 million people a year, causing typhoid fever – also known as enteric fever. It is a major health problem, particularly in areas such as Bangladesh, India and parts of Africa. Although two vaccines are widely available, they give only limited protection, which runs out after a few years. Additionally, a growing number of people in South-central and Southeast Asia are developing paratyphoid fevers, against which there is no licenced vaccine.

Developing countries need a combined long-lasting vaccine that can be produced cheaply for preventative programmes, in particular for children and young adults, who make up most typhoid cases. The EUREKA network project TYPHIVAC has completed an important first step – and at the same time improved the drug-development capacity of the Portuguese biotechnology sector.

Innovative production

Led by Genibet, a Portuguese SME, the project has implemented a simple pilot-scale method of producing vaccines against Salmonella Typhi and Salmonella Paratyphi A, the bacteria most commonly responsible for typhoid and paratyphoid fevers respectively. This pilot-scale manufacturing was done in accordance with good manufacturing practices (GMP) and under a fully documented system, thus allowing easy technology transfer to other organisations.

Genibet produced these with Novartis Vaccines Institute for Global Health S.R.L. and Instituto de Biologia Experimental e Tecnológica (IBET). Novartis shared its experience on vaccines, scaling up and process documentation while IBET focused on the development and implementation of the analytical procedures for the manufacturing process and its quality control.

The project helped us enter a novel field, to learn and apply new techniques.

Implementation of the Quality Management System and the GMPs was a new skill for Genibet. “The project helped us enter a novel field, to learn and apply new techniques,” says its CEO Raquel Fortunato.

Both TYPHIVAC vaccines are conjugates – vaccines in which the disease antigen is combined with a carrier protein, which boosts the body’s immune response. One uses Vi antigen from the extra-cellular polysaccharide layer produced by an attenuated (weakened) Salmonella typhi strain, the other uses O antigen from a lipopolysaccharide produced by a Salmonella paratyphi strain. In each, the carrier protein is CRM197, a non-toxic mutation of the diphtheria toxin that improves protection compared to traditional carriers.

“Our goal was to keep production costs as low as possible,” says Fortunato. Simplicity was key to their success. “The bacteria are grown in a stainless-steel bioreactor to produce and excrete the active product,” says Fortunato. The product is then purified and mixed with the carrier protein so the two bind together.

From pilot scale to trials

TYPHIVAC is big step in a wider programme to develop a combined vaccine against both fevers. Its vaccines have passed the animal toxicity stage of development at Genibet. They are now being made by Novartis in India for basic safety trials with volunteer humans (Phase 1 trials). Results have been good so far and, all going well, the typhoid fever vaccine should be on the market in a couple of years, says Fortunato.

Public funding allowed Genibet to offer their new GMP service to the vaccine development project at a much-reduced cost, says Fortunato. It also attracted Novartis. “The collaboration was very important for us in terms of the support and visibility it gave us,” she adds. “We came from nowhere to having Novartis as our first customer. We are now well-established with various clients.”

The company has grown from having six employees at the start of the project to 30 and can now run three to four projects at a time. “In part, this is due to TYPHIVAC,” says Fortunato.


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