SHANGHAI – A Chinese vaccine joint venture (JV), Bravovax Co. Ltd., of Wuhan, has taken on the global rights for a rotavirus vaccine to be administered to newborn infants – the first of its kind to protect infants at birth from potentially life threatening diarrhea leading to severe dehydration.

The vaccine, known as Rotashield (RRV-TV), first developed by the NIH, was sublicensed to China's Bravovax by the nonprofit, International Medica Foundation (IMF), of Rochester, Minn. And, according to Leonoard Ruiz, president of IMF, the agreement with Bravovax is important not only for China but for the world.

Rotavirus is practically everywhere, and it infects almost every infant in the world before they are 3 to 5 years old. But, while infants in the developing world who contract a rotavirus may suffer from fever, diarrhea and vomiting, it is seldom fatal. In countries lacking adequate medical care, however, it is estimated that rotavirus-related illness causes 450,000 deaths each year.

Under the auspices of the IMF and the Mayo Clinic, the vaccine passed a phase II study tested in 998 newborns and infants in Ghana, Africa, with results published in the Journal of Infectious Diseases last year.

By coming to China, this vaccine is inaugurating the fortunes of Bravovax, as the earliest candidate in its pipeline.

"We are excited about our sublicense for the world's first rotavirus vaccine for newborns that has superior attributes over the currently marketed rotavirus vaccines," said Wu Ke, managing director of Bravovax.

Although just starting out, Bravovax is aiming high. "Our plans are to be a global leader in providing a safe and cost-effective vaccine against diarrhea caused by rotavirus," said Ke.

THE ROTASHIELD ADVANTAGE: IMMUNIZATION FROM BIRTH

Currently there are two vaccines available for rotavirus, Rotateq from Merck & Co. Inc. and Rotarix from Glaxosmithkline plc, administered after an infant is 2 months old. Those currently generate sales of $1 billion, representing a significant global commercial market as well developing market need through the World Health Organization (WHO) and Global Alliance for Vaccines and Immunizations (GAVI).

But Rotashield, administered from the start of an infant's life, may offer several distinct advantages.

Infant mortality due to complications of rotavirus is high in the first months of life, and closing the protection gap by immunizing as early as possible can save lives.

According to statistics provided by Ruiz, 1-month-old infants make up 17.4 percent of rotavirus-related deaths that occur in the first year.

In China alone, rotavirus gastroenteritis causes an estimated 329,000 hospitalizations and 4,900 deaths in infants annually. Early immunization could mean a further 850 lives saved if vaccinated from birth.

In a surprising twist, administering the vaccine as early as possible has other benefits as well.

"If we can use this vaccine at a very early stage, maybe we can avoid adverse reactions," Bravovax's Ke said.

Ruiz added further that "providing the first dose of a rotavirus vaccine to neonates may also help reduce or eliminate the increased risk of vaccine-associated intussusception, which is associated with the current rotavirus vaccines."

That is a significant reversal from 15 years ago, when Rotashield was pulled off the shelves in the U.S. by Wyeth after a year on the market. Then it was believed that the vaccine was the cause of intussusception, an intestine blockage requiring hospitalization, in one of 12,000 vaccinated infants. (See BioWorld Today, April 7, 2008.)

"The vaccine is quite safe," Ke said, "but 10 years ago people did not know much about intussusception."

Rotashield has also had to overcome other skeptics as well, concerned that being administered to newborns render it ineffective due to interference from maternal antibodies or breast milk, or that neonates' immune systems would be too immature.

"We have now successfully proven that Rotashield can generate a protective immune response against rotavirus gastroenteritis when the first dose of the vaccine was administered to newborns (the clinical protocol was to deliver the first dose between birth and 29 days of age, a very practical age range for clinics around the world) and the second dose before the infants were 60 days old," said IMF's Ruiz.

Lastly, from the perspective of administering the vaccine in developing world conditions, Rotashield has another advantage: It does not require a cold chain. The vaccine is freeze-dried and stable at room temperatures for two years. Before being orally administered, it is reconstituted with a liquid buffer to help neutralize infant stomach acid.

A CHINESE FIRM GOING AFTER GLOBAL STANDARDS

Ke explained to BioWorld Asia that his team has been in discussions with IMF about Rotashield since 2011, when Shanghai Bravobio, the company he founded, obtained a domestic license for China.

Shortly afterward, Bravobio got a shot in the arm when it formed Bravovax, a JV with Humanwell Healthcare Group Co., also of Wuhan, a large publicly listed company that leads in Asia in anesthetics, fertility and Uyger medicines, with branches in biologics, central nervous system drugs, traditional Chinese medicine, medical devices and diagnostics.

Bravovax has become the vaccine arm of Humanwell, with the Bravobio team – many of whom were formerly from Shanghai Zerun Biotechnology Co. Ltd., a subsidiary of Walvax Biotechnology Co. Ltd. – providing technical expertise and pipeline candidates, and Humanwell chipping in the financial backing and the corporate infrastructure of a listed company.

Given that Bravobio got its start bootstrapping with the founding executives' own funds, the Humanwell contribution has been a game-changer for the company.

According to Ke, "Humanwell committed to give sufficient funds to support growth, no matter the development stage or amount, whether it be industrial production or international marketing."

That will be necessary for Bravovax to achieve the international standards of vaccine development it is seeking and necessary to get global acceptance for Rotashield. Although the global sublicense excludes the developed markets of the U.S., European Union and Japan, it includes India and Africa, countries with high rotavirus mortality.

As a nonprofit, the IMF is committed to ensuring that safe and effective vaccines are affordable for needy populations. Although the deal terms with Bravovax were not released, that meant a special agreement had to be developed in order to be mutually beneficial to both parties and to secure accessibility.

"We developed two sets of criteria for our license agreement," said Ruiz. "One set of criteria was related to future sales to organizations like UNICEF, GAVI, etc., to ensure that an affordable vaccine was available to resource poor areas of the world, and a different set of criteria was developed for commercial sales in the future."

In the long run, Bravovax is seeking to follow the standards of the International Committee of Harmonization (ICH), Ke said. To date, no Chinese vaccine has achieved that standard. While the Chinese GMP for vaccines is, in fact, very strict, it is often compromised in practice.

China has had only one vaccine approved for international use, the Japanese encephalitis vaccine granted pre-qualification (PQ) status by the WHO last year. For the Chengdu facility that manufactured the vaccine, it took an investment of close to $50 million and eight years to achieve the quality standard required for PQ. (See BioWorld Asia, Oct. 23, 2013.)

Ke is undaunted that the ICH standard is even more stringent than the WHO PQ. "From the beginning, the mindset of Bravovax is quite different from other Chinese vaccine companies," he said.

It will be a long haul for the company, which has to overcome the challenge of testing the vaccine on Chinese infants, something the CFDA has been traditionally reluctant about permitting. But Ke remains optimistic, predicting it could take five to six years before Bravovax is able to obtain market approval in China, which would be necessary to allow parents to purchase the vaccine.

Typically, after a vaccine is on the market for a period of five to 10 years with a good record of safety and efficacy, the CFDA will consider adopting a vaccine into the national program. Ke said he is hopeful that might be accelerated, given that in 2009, the WHO proposed all countries include a rotavirus vaccine in national immunization programs.