A new Cuban vaccine has just been announced against the bacteria that causes meningitis and pneumonia primarily in children up to five years of age. The breakthrough vaccine, produced with an innovative technology that was jointly patented in 1999 by the University of Havana and the University of Ottawa, is also the world's first human vaccine with a synthetic antigen.

During a keynote address at an international biotechnology congress that just concluded in Havana, Dr. Vicente Verez Bencomo, head of the University of Havana's Synthetic Antigens Laboratory, said that after 14 years of research and tests, the new vaccine is finally in production and will become part of the country's national vaccination program as of January 1st.

"The most important part of this project is that we're contributing to the health of children," he said.

The Cuban expert explained that the vaccine protects against Haemophilus influenzae type b (or Hib), a bacteria that causes nearly 50% of all infections, some of which lead to deafness and mental retardation, in under five-year-olds worldwide. Annually, over 500,000 children die from Hib.

"Only 2% of the world's children are currently protected against Hib", says Verez, who studied chemistry in the former Soviet Union and France.

Before 1988, when conjugate Hib vaccines were first introduced, Hib disease was the most common cause of bacterial meningitis in children in the U.S. By the early 1990s, a drastic reduction of over 95% was seen in the incidence of Hib disease. But this vaccine, based on a complex process using fermentation of bacterial culture, was expensive to produce - making it virtually impossible for poorer countries to obtain. As a result, most of thedeaths from Hib are now found in developing countries.

In January 1999, Cuba began its first national Hib vaccination campaign, purchasing the expensive Hib vaccine from overseas at a cost of US $3 per dosage. It's partially because of this high cost that Cuba began searching for a low-cost alternative that could be produced on a large scale. But there are other reasons as well. As Verez says: "What could be more precious for society than to have healthy babies."

Biotechnology, Cuban style

How is a poor, third world nation such as Cuba able to develop such a sophisticated vaccine? The answer is not hard to find. Since the 1959 revolution, the cornerstone of the country's social development has been education and health care. From the 1980s on, the Cuban government has invested well over US $1 billion to develop modern vaccine laboratories and an immense biotechnology complex.

The results have been impressive: a meningitis meningococcus groups B and C vaccine, a Hepatitis B vaccine, the famous PPG which significantly reduces cholesterol levels, monoclonal antibodies that prevent the rejection of transplanted organs, recombinant interferon, and now a low-cost synthetic Hib vaccine. There are also presently 150 biotech patents in Cuba of which 66 are in other countries, overseas quality certifications of Cuban biotech products, technology transfers abroad, and a joint project with GlaxoSmithKline for the introduction of the meningitis B vaccine into Europe and possibly the U.S. Today, Cuba exports pharmaceutical products to over 50 countries per year. Last year, annual sales totalled about US $30 million.

The reason Cuba's biotech development has been so successful is not only because of large government investments. It's also in the organization and overall orientation. Rather than functioning independently, Cuban biotech and pharmaceutical industries are part of the national health care system. With a focus on developing a national research capacity based on Cuban scientists and professionals, the first priority of biotech research is the domestic market, meaning that the Cuban people themselves directly benefit from the country's medico-scientific expertise. This concern with the well being of the local population goes hand in hand with developing new medical products for export. The Cuban biotech industry is also an integrated system from research to post-marketing, and includes the development of spin-off companies such as Heber Biotec S.A, responsible for commercializing all pharmaceuticals both nationally and internationally. Finally, Cuba's biotech industry is characterized by national collaboration rather than individual competition.

The development of the Hib vaccine is a case in point. "It's a collective achievement of the accumulated intelligence of our country", says Verez, explaining that to produce this vaccine involved over 300 investigators and technicians and several different Cuban biotech institutions. The Synthetic Antigens Lab worked on making the synthetic antigen, the Finlay Institute worked on the protein carrier, the Centre for Genetic Engineering and Biotechnology (CIGB) joined the two compounds and the National Centre for Bioproducts bottles the vaccine in dosage-size flasks which will be commercialized under the registered name of Quimi-Hib.

Canadian Collaboration

Canadians can also feel proud that they too played an essential and key role in contributing to develop the world's first synthetic vaccine at a critical moment of the process.

What is unique about the new Hib vaccine is that it's made with a chemically produced antigen. An antigen is the smallest substance that antibodies need to recognize so that they can trigger the immune system to take action. A vaccine produced from fermented bacterial cultures always carries the risk, however slight, of infection by the disease. But with a chemically-produced synthetic antigen, the immune system is fooled into thinking it's being hit by the actual bacteria and develops the necessary antibodies. This is the beauty of synthetic vaccines: they're completely safe.

So why has it taken so long to produce a synthetic vaccine? Especially when Cuba's Synthetic Antigens Lab was only one of approximately ten labs and companies worldwide which had succeeded in developing the Hib synthetic antigen. The answer has to do with the new technology involved in producing the antigen.

Enter Canadian Professor Rene Roy who, when he first met Verez at a 1994 International Carbohydrate meeting in Ottawa, was on staff at the University of Ottawa. A year later, Verez invited Roy to a similar meeting in Havana -and the seed was planted for what was to become one of the most fruitful scientific collaborations in the development of the vaccine. The problem: how to innovate and simplify the ongoing Cuban process of binding the phosphates in the antigen in a way not pursued by its competitors for a successful and a patentable approach. Headed by Roy, the two chemists and their respective universities wrote up a proposal that was funded by the World Health Organization (WHO), and after two years of research the answer was found.

"I figured out a way to do the phosphate bindings that works like a continuous zipper, rather than doing the bindings one at a time," explained Roy during an interview last week at the biotechnology meetings.

This "zipper binding technique" was a novel discovery, as it meant fewer steps - and hence a technology that was both simpler and competitive with the existing conventional technology - in preparing the antigen. Once the problem was solved, the two inventors filed a patent first in Cuba, and later in other countries. The discovery is co-owned on an equal basis by the University of Ottawa and the University of Havana.

After bonding the synthetic antigen, it was ready to be joined with the protein carrier to produce a vaccine. But before it could be considered a success, it had to be tested.

Clinical Trials

Clinical testing of any vaccine involves three basic stages: safety of the process, efficacy of the vaccine with a limited population and finally, efficacy with the target population.

From earlier tests on rabbits, the Synthetic Antigens Lab already knew that the synthetic antigen was recognized by the antibody system. They also determined that the antibodies could kill the Hib bacteria. But now began the most critical phase: testing the synthetic vaccine with human beings.

"I was the very first volunteer," said Verez. "but when my immune system showed no response after the first week, we got worried. By the second week, though, the response was good."

This phase of the work - clinical testing - was designed and organized by the Havana-based "Pedro Kouri" Institute of Tropical Medicine and CIGB, and monitored by Cuba's Clinical Trials and Regulatory Affairs Department. Internationally established procedures for testing vaccines were used, such as the double blind method whereby neither the administering nurse nor the subject (nor lab technicians who later test the results) knows who gets the vaccine and who gets the placebo, and using control groups which receive the existing commercial vaccine. Cuban specialists also visited the Federal Drug Administration in Washington DC, to talk with American specialists in the FDA's Centre for Biological Evaluation and Research about how they evaluate vaccines.

Starting in 1999, seven independent clinical trials were carried out on the new vaccine. The first two trials involved adults, all volunteers - mainly from the Synthetic Antigens Lab - divided into two groups of about 40 people each. Then came two trials with four- and five-year-olds. Written consent was required from both parents; if one or both wanted to abandon the test and withdraw their child, they were free to do so. In total, about 1,100 children participated in these two trials. These and subsequent tests involving children were done in the central province of Camaguey, nationally recognized for its high level of organization.

Finally came the tests with the target population: two-month-old babies. Again, both parents had to agree. If they did, their participation began before birth of their child, so that the reason for the clinical tests could be carefully explained and understood. A total of about 1,100 babies received the vaccine at two, four and six months of age, making this the longest clinical trial of all.

"The trials with nursing babies were the most emotional of my life," said Verez during a press visit to the lab "and the strength of the parents was impressive for us to see."

The seventh and last trial, carried out with 18-month-old toddlers - the same children from the two previous trials - tested the final booster shot vaccine. The children were found to be 100% protected, with their antibodies having increased by a factor of ten. This was an important result as it showed that the memory response of the vaccine was working.

In May 2003, with all the data from the clinical trials available, the result was conclusive: a 99.7% success rate among all children in developing the required antibodies, and at a level exceeding internationally recognized standards of efficacy for human vaccines.

On November 6, the new Hib vaccine was registered in Cuba, and, says Verez, it's in the process of being patented in other nations. Preparations are also underway to have the vaccine certified by WHO. If granted, the synthetic vaccine would join the ranks of Cuba's Hepatitis B vaccine, which since December 2001 has had a pre-qualification status from WHO - the first vaccine in Latin American to receive this recognition - meaning that it can participate in tenders with WHO, the Pan American Health Organization, etc.

Production and Marketing

Today, Quimi-Hib is being produced in Cuba in a new modern plant at CIGB which has been outfitted with state-of-the-art technology. To date, some 300,000 doses have been produced; for Cuba, it's estimated that about 3.5 million doses will be needed annually. But with overseas sales a serious prospect, the plant has been designed to eventually produce hundreds of millions of doses. And Heber Biotec - which owns the license not only for selling Quimi-Hib but for commercializing all CIGB products and projects - is already starting to think through its marketing strategy.

Yet even in its approach to marketing, Cuba offers an interesting twist to the norm. "Our objective in developing this vaccine is to lower infant mortality," says Dr. Carlos Manuel Mella Lizama, vice general manager of Heber Biotec, "not to make money. Of course, we can't give the vaccine away. We must sell it. But money isn't the objective of our biotech industry, it's the means."

Mella explains that some of Heber's overseas partners say that Heber functions like a transnational corporation because it has business relations in 60 countries and makes US $30 million a year from sales. "But we're substantially different from TNCs which serve under their own banners", continues Mella, "because we work under the same banner as our country and share social and human objectives rather than purely financial ends."

To illustrate his point, Mella notes that the University of Havana and the University of Ottawa have jointly agreed to waive any royalties from the sale of Quimi-Hib either in Cuba or in epidemic situations in developing countries. "This decision is part of our struggle to defend children in the Third World," says Mella. "If you don't care for the children, you don't care for the future."

Canadian Rene Roy, who since January 2003 has been with the Chemistry Department at the University of Quebec in Montreal, echoes this sentiment. "I feel proud of this new vaccine and of the fact that the end product of our work is geared to infants."

And what of the future for Cuba's biotech industry? At present, Cuba is working on 29 other vaccines besides Hib, including developing an affordable alternative - perhaps another synthetic vaccine - for protecting children against pneumococcus, a disease which kills three million children annually the world over. The existing vaccine, produced in the U.S., costs US $250 for four doses. The overall objectives of Cuba's vaccine projects are to treat masses of people, provide protection, and make vaccines easily accessible to poor countries.