Zika vaccine Phase I trial to begin next month in India

measuring microcephaly. Photo WHO

The Phase I trial will not involve pregnant women.

Bharat Biotech International Ltd in Hyderabad will start a Phase I clinical trial of Zika virus vaccine (MR 766) in two centres in India next month. The inactivated  vaccine being tested in humans will be an African Zika virus strain. “We have already got the approval from DCGI [Drug Controller General of India] in March to carry out the Phase I clinical trial,” says Dr. Krishna Ella, Chairman and Managing Director of Bharat Biotech.

It will be a randomised, placebo-controlled, double-blind trial involving 48 adults, both men and women (who are not pregnant). Each volunteer will receive two doses of the vaccine on days 0 and 30 and followed-up for a year for both safety and immune responses. Three different dose ranges (2.5, 5 and 10 microgram) will be tested.

There will be three arms in the trial and each arm will get one of the three different dose ranges. There will be 16 subjects per arm.

The Phase I human clinical trial is being initiated based on the promising results seen in animals trials. In the animal trials, two doses of the vaccine made using an African Zika virus strain conferred 100% protection against mortality and disease in mice. The protection was the same when the mice were infected with an Asian and an African Zika virus strains.

While the viral load was “undetectable” in the case of vaccinated mice, the amount of virus in unvaccinated mice shot up four days after being infected. All the unvaccinated mice died eight days after infection by the African strain of the virus and 12 days after infection by the Asian strain.

Published in The Hindu on April 18, 2017

Bharat Biotech’s Zika virus vaccine confers 100% protection in mice

zika-microcephaly - Photo WHO

The vaccine made using an African strain confers 100% protection against infection and mortality caused by Asian and African Zika virus strains.

The Hyderabad-based Bharat Biotech’s killed (inactivated) Zika virus vaccine using an African strain (MR 766) has shown 100% efficacy against mortality and disease in animal studies. A ‘killed virus vaccine’ or ‘inactivated vaccine’ contains virus that has been grown in culture and then killed using physical or chemical processes. The whole virus was used for developing the vaccine.

Two doses (5 and 10 microgram) of the vaccine given through intramuscular route on days 0 and 21 to mice were found to protect the animals against Zika virus seven days after the second vaccination. The vaccine was found to confer 100% protection against infection caused by an Asian Zika virus strain as well as by the African Zika virus strain.

All the animals that were not vaccinated died eight days after infection by the African strain of the virus and 12 days after infection by the Asian strain. All the mice that did not receive the vaccine showed progressive morbidity before succumbing to infection.

While all the animals that received the vaccine exhibited “undetectable” viral load, the amount of virus present in animals that did not receive the vaccine peaked four days after being infected with either the African or Asian Zika virus strain. The results of the study were published in the journal Scientific Reports.

AG129_mouse

The AG129 mouse is highly immunocompromised.

“The vaccine was developed using the African strain of the virus. It is important to prove that the vaccine developed with the African strain also protects against Zika infection caused by the contemporary Asian strains of Zika virus. Importing the contemporary Asian strains into the country was difficult, and hence the vaccine challenge studies with Asian strain had to be outsourced to a CRO in the U.S.,” says Dr. K. Sumathy from Bharat Biotech and the first author of the paper.

A particular kind of mouse — AG129 — which is highly immunocompromised and hence highly susceptible to virus infection was used for studying the protection conferred by the vaccine against Zika virus, disease pathogenesis and mortality. All the AG129 animals that received the vaccine showed 100% protection against the virus, demonstrating the superior efficacy of the vaccine.

Immunogenicity studied

Additionally, the level of immune response induced by the vaccine was also studied using another kind of mouse model — Balb/c mice. Unlike the AG129 mice, this mouse model is immunocompetent and elicits full spectrum of immune response. Animals that received the vaccine developed Zika neutralising antibodies on day 14 after the first dose and a week after the second dose. When the animals were infected with Zika virus post-vaccination, the virus in the vaccinated animals was “undetectable”, while 72-96 hours after infection it peaked in animals that did not receive the vaccine.

“In both the mice models, the vaccine-induced protective immunity against virus challenge was observed,” says Dr. Sumathy. “The vaccine was made only with the African virus strain, but the vaccinated mice was challenged [infected] with both the African and the Asian strains. Our vaccine offered equivalent protection against challenge with both the African and the Asian strains of Zika virus.”

Though 5 and 10 microgram of the vaccine were tested, the amount of antibodies elicited by the higher dose was “not significantly” higher than that elicited by 5 microgram of the vaccine, says Dr. Sumathy. Vaccination protected the animals against Zika virus and disease up to 14 and 20 days after being challenged with the virus.

Passive immunisation

Bharat Biotech also carried out passive immunization studies to show that the Zika vaccine-induced antibodies confer protection against the virus in mice that were exposed to the virus. Rabbits were vaccinated with the vaccine and the vaccine-induced antibodies were given to mice. While no virus was detected in mice 24-144 hours after passive immunisation, the viral load peaked 72-96 hours in mice that did not receive the vaccine-induced antibodies.

“Our study shows that the choice of Zika virus strain may not be a limiting factor in vaccine development,” she says.

Published in The Hindu on April 17, 2017

Indigenous vaccine against diarrhoea virus ‘safe’

A Phase III randomised, double-blind, placebo-controlled trial of 116E rotavirus vaccine undertaken in infants at three centres in India was found to be safe. It had modest efficacy of 56.4 per cent against severe rotavirus gastroenteritis during the first year of life. The results were published in The Lancet on Wednesday.

With about 75,000 to 1,22,000 deaths per year, India accounts for a quarter of rotavirus deaths in the world. Rotavirus diarrhoea accounts for almost 10 per cent of all under-five deaths and it is responsible for about 39 per cent of diarrhoea-related admissions in the country. About 70 per cent of admissions take place in the first year of life.

The Hyderabad-based Bharat Biotech International, which had undertaken the clinical development of the vaccine and would manufacture it, has committed to make the vaccine available at not more than $1 per dose for government procurement.

The trial took place between March 2011 and November 5, 2012 in Delhi (urban), Pune (rural) and Vellore (rural and urban). Three doses of the oral vaccine were given at ages 6-7 weeks, 10 weeks and 14 weeks respectively. Other childhood vaccines were given concurrently.

Over 4,500 infants received the oral vaccine, while over 2,250 received a placebo. But for the primary per-protocol efficacy analysis, only over 4,350 vaccinated infants and nearly 2,200 infants who received a placebo were included. Though 25 deaths were reported in the vaccine arm and 17 in the placebo group, the deaths were found to be unrelated to the vaccine, the paper notes.

“The vaccine is very close to getting licensed in India,” said Dr. Krishna Ella, Chairman and Managing Director of Bharat Biotech International. “We have developed a dedicated manufacturing facility for rotavirus vaccine. It will be ready in 4-6 months.”

The vaccine was developed by the “combined expertise and interests” of investigators from 13 institutions.

Published in The Hindu on March 14, 2014