Four flu vaccine manufacturers have started or will soon start clinical trials on H7N9 vaccines, with four more expected to conduct trials in the late fall or early winter, says Dr. Robin Robinson. The work will cost the U.S. government about $100 million.
GSK, which holds the major portion of Canada's pandemic vaccine contract, is one of the manufacturers working on the project. It is making H7N9 vaccine at its plant in Ste-Foy, Que., but will conduct its clinical trial in the United States.
Most of the vaccines will be tested with an adjuvant, a compound that boosts the impact of the vaccine and allows smaller doses to be used per person — a result known as antigen sparing.
"We're just trying to get some indication that the vaccines are immunogenic and certainly well tolerated and that the adjuvants are providing some antigen-sparing effect," Robinson says, adding that preliminary results could be available in October or November.
Robinson is the director of the Biomedical Advanced Research and Development Authority, the division of the U.S. Department of Health and Human Services tasked with spurring the development of vaccines, drugs and diagnostic tools that might be needed for public health emergencies.
The department decided to commission manufacturers to make and study H7N9 vaccine earlier this year after the new avian flu strain exploded in eastern China.
To date there have been 135 confirmed infections, 44 of which have been fatal. There have only been two cases over the summer, but experts worry the infections will pick up speed when temperatures start to drop in the fall.
When H7N9 cases proliferated at an alarming rate in early April, many flu experts worried whether a usable H7N9 vaccine could be made. The few previous studies of vaccines against flu strains carrying an H7 hemagglutinin — the protein on the virus's shell that gives it the H portion of its name — were dismal.
Even with massive doses — 12 times as much vaccine as used to protect against strains of seasonal flu — the vaccines didn't trigger much of an immune system response. Needing huge doses per person would severely limit the amount of vaccine available globally if a pandemic with H7N9 were to occur.
"This was always one of the real gaps we've had," Robinson says.
"We've been successful with (vaccines against) H9s, H5s, H1s, H2s, H3s and so forth. But H7s — we had tried before and we've just not had very good luck.''
But in the past few months there have been glimmers of hope. Animal studies have shown that when H7N9 vaccine is mixed with an adjuvant results were better. Just last week the Chinese flu vaccine maker Sinovac announced its trial H7N9 vaccine had been effective in animal studies and human testing would soon begin.
Robinson acknowledges he is more optimistic at this point that an H7N9 vaccine that has a practical dosing regimen could be made.
"If I had not seen some of those data, I would probably be as pessimistic as I would have been last year. But some of the animal data is promising and gives a little bit of hope there," he says.
Doses as small as 3.75 micrograms — one quarter of the dose used per strain in seasonal flu vaccine — and as large as 30 mcg will be tested, in a two-dose regimen. Because the virus is new to the human immune system, it is expected two doses will be needed.
While the U.S. did not use adjuvants during the 2009 H1N1 pandemic — Canada did — it may need to go that route if H7N9 goes on to cause a global outbreak.
"If it takes more than 15 micrograms per dose, then we certainly would rely on adjuvants and the antigen-sparing effects of adjuvants. And hopefully these newer ones will work," Robinson says.
"And if a pandemic were to emerge, then we would be able to have that as a choice to go forward."
Flu vaccine expert Dr. John Treanor says he expects the trials to show adjuvanted H7N9 vaccine will work.
"All the avian viruses are tough to generate antibody to," says Treanor, head of infectious diseases at the University of Rochester (N.Y.) Medical Center.
"So I would imagine that a standard, unadjuvanted H7 vaccine will probably not be very immunogenic, just like the H5(N1 vaccine) wasn't. But I don't think there's anything special about H7 that makes it different from anything else. There might be — but at the moment I don't think there's real data that supports that concept."
Novavax, a company which doesn't currently produce a licensed seasonal flu vaccine in the U.S., was the first to complete production of its H7N9 trial vaccine, Robinson says, and the company started its clinical trial in July.
Sanofi Pasteur, Novartis and MedImmune have also made their vaccine batches and testing of their products will begin soon, Robinson says.
The four companies still to make H7N9 vaccine are GSK, Australian manufacturer CSL, Protein Sciences and Vaccinate, which also does not have a licensed seasonal flu product yet in the United States.
The MedImmune vaccine contains live virus, the only one of the eight to do so. That presents special challenges for testing it, says Treanor, who will do part of the work on the MedImmune vaccine.
The virus in the vaccine is weakened, which allows it to provoke the immune system to produce antibodies against H7N9 without giving people receiving the vaccine an active infection.
But there is a theoretical risk that someone getting the vaccine could be simultaneously infected with a seasonal flu virus, which could lead to the viruses swapping genes and forming a hybrid, Treanor says. If that hybrid carried an H7 hemagglutinin but had the spreading capacity of seasonal flu, it would pose a real pandemic risk.
So testing of the live virus vaccine will be done in isolation units, at the University of Rochester and at Johns Hopkins University in Baltimore, Md.
"The subjects, once they get vaccinated, have to stay in a room where they have no contact with other people until they're not shedding the vaccine virus anymore," Treanor says.
Time is of the essence for this study, if results are to be produced this fall. In order to further lower the risks posed in testing the live virus vaccine, tests like these are not done during flu season.
"The problem is we want to do two doses. So if we don't get started before October, it's going to be very difficult to get that done before we start seeing flu in Rochester," Treanor says.