At the peak of the dengue season, with New Delhi alone reporting over 7,600 cases and over 35 deaths, Dr. Kiran Mazumdar-Shaw, Chairperson of Biocon Limited, Bengaluru, on October 30, tweeted: “Govt is not committing to fund balance $4 m for dengue vaccine trials — disgraceful when there’s a national crisis.”
India’s dengue vaccine candidate (DSV4), developed by the New Delhi-based International Centre for Genetic Engineering and Biotechnology (ICGEB), is one of the most exciting developments currently under way in our scientific landscape. The international scientific community is following very closely the development of the novel vaccine. But for all the promise that the vaccine offers, the project is marred with challenges — apparently of the money and the monkey kind.
Let’s talk about the monkeys first.
The indigenously developed vaccine candidate has reached a critical milestone where preliminary animal trial results appear promising but further study of the vaccine on monkeys appears challenging for several reasons.
To put it simply, in India, the specific kind of monkeys needed for the trials are only few in number and plenty of time is required to find them.
As part of the preliminary trial on animals, the vaccine was tested in about 400 mice and six monkeys. While the vaccine conferred 100 per cent protection against dengue in mice, antibodies that prevent the entry of all the four closely-related dengue viruses — DENV-1, DENV-2, DENV-3, and DENV-4 — into human cells were produced in the monkeys.
Since none of the vaccinated monkeys was purposely infected with dengue virus, there was no way of knowing the level of protection offered by the vaccine against the four dengue viruses and for how long the protection lasted in the monkeys. It is also not known whether the monkeys studied were earlier infected with flavivirus — dengue is one of the flaviviruses.
So, the next step is to conduct trials on more monkeys to get sufficient information about the vaccine. “The number of monkeys to be studied depends on the questions asked and the extent to which data on monkeys are required,” claims Dr. Navin Khanna of ICGEB who has been working on developing a dengue vaccine since 2007. “Duration of protection, level of protection and studying monkeys that were infected and never infected with flavivirus [flavi naïve] may be required.”
India may have innumerable monkeys in the wild but carrying out studies on them may prove difficult as finding monkeys that have never been infected with flavivirus, those which can be called flavi naïve, may be hard. “Monkeys in India may already be infected with flavi viruses. We may get less than 10 flavi-naïve monkeys after screening 100 animals. So it will delay the trial and also make it expensive. But Puerto Rico has colonies of monkeys that are flavi naïve,” Dr. Khanna says.
The road ahead
The plan is to carry out animal studies at Global Vaccine Inc, North Carolina, to save time and money.
According to Dr. Khanna, it will cost $3 million to study 60 monkeys. An additional amount of $2 million may be required if more aspects such as duration of protection are to be studied. “The goal is to have a good non-human primate challenge experiment [purposely infect the animals with the virus] without compromising on the scientific data but at the same time doing it economically and quickly,” Dr. Khanna underlines.
While a laboratory-grade material is sufficient to carry out immunogenicity studies on monkeys to know if antibodies are produced and whether they are able to protect the animals, a good manufacturing practice (GMP) badge is a must before undertaking the 28-day duration toxicity studies in rats and rabbits, required before Phase-I trials in humans. Dr. Khanna estimates that GMP badge and toxicity studies will cost another $2-3 million; in all, the bill will amount to a modest $7-10 million.
The development of the Indian dengue vaccine, which was initially supported by the Indo-U.S. Vaccine Action Program, is currently being supported by the Wellcome Trust under the Affordable Healthcare India (AHI) scheme until January 2016.
Funding gap
But what the vaccine makes up for in science, it lacks in funding. The Wellcome Trust funding is not accepting any new proposal under the Affordable Healthcare India (AHI) scheme. For now, the project has been given a short lease because Infosys founder N.R. Narayana Murthy and Infosys Foundation, in a refreshing gesture, provided $2 million funding for taking the vaccine candidate forward.
Forget fast-tracking, with no culture of developing and funding, promising, novel vaccines in India, particularly for a disease that affects millions and kills thousands across the world, India included, Dr. Khanna is tapping diverse sources for the balance amount.
“We have submitted a new proposal last week to Wellcome Trust for exploring any possibility of further funding opportunities from their other schemes. We may also go back to the Indo-U.S. Vaccine Action Program for funding,” he said. “We can take the candidate forward faster with private funding.”
However, Prof. K. VijayRaghavan, Secretary of the Department of Biotechnology, reassured that providing funding in a step-wise manner based on the results at each stage of the trial will not be a problem. “There are many ways to raise resources as specific needs emerge,” he underlined through an e-mail to The Hindu.
“I see no problem in funding a good proposal, which is reviewed and evaluated, to be supported in the best place anywhere to get speedy results,” added Prof. VijayRaghavan on whether the government would allow animal studies to be done abroad and if it will part fund such trials.
Despite the experiment not being fully-funded, Dr. Khanna plans to take it to the next stage of the experiment, using the $2 million provided by Mr. Murthy and Infosys Foundation. Even as this money is being spent, he is seeking additional funding for the next stage.
It is a pity that Dr. Khanna has to scout for funding for trials despite the vaccine candidate proving to be safe, affordable and efficacious. On August 21, 2015, with help from the Wellcome Trust, Dr. Khanna and his team at ICGEB filed an international patent on the design of the vaccine candidate. “ICGEB owns the patent,” he clarifies.
Discussion are already on with two Indian companies to manufacture the vaccine. “Developing novel dengue vaccines require a lot of domain experience and it would be ideal to work with companies who have dengue domain experience. As we work, I am sure Indian companies will likely collaborate,” said Prof. VijayRaghavan from the Department of Biotechnology.
Unique vaccine
It may be a few years before the vaccine developed by ICGEB becomes commercially available. Of the several other players developing a vaccine against dengue, Sanofi Pasteur is a frontrunner, having completed the Phase III trial in humans. However, Sanofi’s vaccine (CYD-TDV), which may soon become available, seems to have some critical problems.
On the other hand, based on preliminary results, the ICGEB’s vaccine candidate appears to be free from all the shortcomings seen in Sanofi’s candidate and also in other vaccines currently undergoing trial. The reason for that is the unique approach adopted by Dr. Khanna and his team to develop the vaccine. Making a marked departure from the conventional approach, ICGEB has used only a few key proteins of each dengue serotype to elicit immune response against all the four dengue-causing viruses. Thus the vaccine can prevent the entry of all four dengue causing viruses into human cells. The key proteins used in the vaccine are genetically engineered in yeast cells and commercial production will become easy and affordable as it will be a single-stage process.
Compare this with the approach adopted by Sanofi and others — the whole virus in a live, weakened form is used to elicit immune response. Since the vaccine has to protect against all the four serotypes, the conventional approach has been to use the whole virus of all the four closely-related dengue causing viruses.
The biggest shortcoming faced by using whole viruses by Sanofi and others is the potential to generate undesirable antibodies. The vaccine-generated undesirable antibodies can prove counterproductive by facilitating the entry of dengue virus into human cells, thereby causing severe disease. Since, the ICGEB’s candidate uses only the vital proteins the vaccines do not elicit the undesirable antibodies, the preliminary results show.
Sanofi’s dengue vaccine has other problems too. First, Sanofi’s vaccine has not been uniformly effective against all the four dengue causing viruses. In particular, the efficacy against DENV-2 serotype that is very prevalent in India was lower than the other three serotypes. Second, studies show that though the vaccine was primarily intended to prevent infection (prophylactic) in people who have been previously infected with dengue and who those have never been infected with dengue (dengue naïve), it failed to protect those who have never before infected with dengue. Effectively, the vaccine can only be used to boost the immune response in people who have already been infected with dengue earlier.
Finally, for reasons unknown, during the trial there was higher incidence of hospitalisation of young children (below five years) two years after vaccination.
India has woefully under-performed when it comes to developing an indigenous vaccine. Till date, not a single vaccine — for any disease — has been indigenously designed, tested or manufactured in India. The ICGEB’s dengue vaccine candidate offers a great potential to become the first one, offering promise to provide protection against a disease that has become a pressing public health concern in over 100 countries, both developed and developing.
Over 2.5 billion people, nearly half the world’s population, are at risk of contracting the disease each every year. In 2010, there were about 400 million infections occurred worldwide, of which 34 per cent were in people living in India. According to an April 2013 paper in the journal Nature, India is an epicentre of dengue with about 33 million cases in 2010.
Besides being one of the fastest spreading vector-borne diseases, any of the four closely-related dengue viruses can cause the disease and infection by one serotype does not offer protection against other dengue causing viruses.
