The quest for a broadly protective or "universal" influenza vaccine suffered a setback recently when the US Biomedical Research and Development Authority (BARDA) determined that industry plans submitted in response to a formal request for proposals (RFP) fell short of the government's requirements, according to BARDA Director Robin Robinson, PhD.
"From the RFP we had a number of proposals and unfortunately none of those met our minimum mandatory requirements. Some of them were maybe 6 months away from meeting our requirements," Robinson told CIDRAP News in an interview about BARDA's pandemic flu preparedness programs.
Robinson said BARDA, which is part of the Department of Health and Human Services (HHS), plans to issue a "broad agency announcement" in October to renew the call for proposals for advanced development of broadly protective flu vaccines. He expects that some of the proposals that didn't meet the requirements will be more mature by then.
In other comments, Robinson said BARDA is supporting development of two vaccines for the H5N8 avian flu virus and hopes to develop a vaccine for the H5N2 virus, in case either of those evolves into a human pathogen. He also voiced concern about the agency's future pandemic flu funding, as bills now in Congress would provide far less than the $170 million the Obama administration has requested for fiscal year 2016.
Robinson also reported that continued testing shows that BARDA's aging stockpile of prepandemic H5N1 vaccines remains potent.
RFP issued in January
The quest for a broadly protective flu vaccine has been under way for many years. The aim is to eliminate the need to retool the vaccine every year to keep up with the mix of ever-evolving flu viruses in circulation. In addition, it is hoped that such a vaccine might be effective when an evolutionary lurch produces the next pandemic flu virus.
Conventional vaccines target the head of the hemagglutinin molecule, a protein that forms part of the virus's coat and that frequently changes in ways that can make it less visible to the immune system. Scientists hope to develop a vaccine that targets a part of the flu virus that is more stable and is essentially the same in different strains within the same flu subtype, such as H3N2.
BARDA issued a draft RFP for "Advanced Development of More Effective/Universal Influenza Vaccines" last December and followed up with the final RFP on Jan 27 of this year. Language in the document called for oral presentations by participating pharmaceutical companies in May.
Robinson said the RFP triggered several proposals from the biopharmaceutical industry, but he said federal regulations bar him from saying how many companies offered them.
The offered proposals "just weren't mature enough. Some of them were almost there," he said. "This is a very tough project to take on, so we want to make sure we can mitigate any risk and find the most promising candidate."
'Good candidates out there'
"We know there are some good candidates out there that just didn't meet the bar yet, but we think they will," he said. "I think there are maybe a half dozen to eight or nine candidates that we're not supporting yet but may be ready over the next year."
The broad agency announcement planned for October will be an open invitation to submit proposals, with no deadline, unlike an RFP, Robinson said. Plans call for making the announcement in early October, before BARDA Industry Day, which will be in mid-October. BARDA officials will make a special presentation about more effective and universal flu vaccines on Industry Day, he noted.
Robinson noted that BARDA is already supporting one broadly protective flu vaccine candidate, a "chimeric hemagglutinin" that was developed by Peter Palese, PhD, and colleagues and is a GlaxoSmithKline project. The agency also is negotiating with another company for a contact on a proposal that was submitted in response to an earlier BARDA announcement, he added.
"Our strategy for the long term is that we need at least four vaccine candidates to get one that could be successful within the next decade," he said. "We know it'll be a long-term process and there'll be a lot of attrition."
Vaccines for avian strains
On other topics, Robinson said BARDA is supporting the development of two vaccines against the avian H5N8 virus, just in case it should gain the ability to infect humans. CSL is making an egg-based vaccine at a facility in Australia, while Novartis is producing a cell-based vaccine in Holly Springs, N.C.
H5N8 and its close relative, H5N2, first surfaced in birds in the United States late last year, and the H5N2 virus devastated many Midwestern poultry farms this past spring. Neither virus has been known to infect humans, but experts say there is no guarantee that won't happen.
As for the H5N2 virus, Robinson said BARDA is waiting for the Centers for Disease Control and Prevention (CDC) to supply a seed strain that can be used to develop a human vaccine.
He noted that HHS has looked at whether BARDA's stockpiled prepandemic H5N1 vaccine would be likely to provide any protection against the H5N8 or H5N2 viruses, since the strains share the H5 type of hemagglutinin.
At the Advisory Committee on Immunization Practices (ACIP) meeting in June, a CDC official said tests showed that neither H5N8 nor H5N2 cross-reacted with an H5N1 vaccine, suggesting that the vaccine would not be protective.
Robinson said the older H5N1 vaccine strains are the most distantly related to the H5N8 and H5N2 viruses. BARDA's stockpile also contains some doses based on a more recent strain, called Anhui, which dates to 2009 and is more closely related to H5N8 and H5N2. He said the CDC plans to test whether the Anhui-based H5N1 vaccine would offer any protection against the other avian strains.
Aging prepandemic vaccines still usable
Robinson also addressed questions about the status of prepandemic vaccines, mainly for H5N1, in BARDA's stockpile, some of which date back roughly a decade. The stockpile is separate from the Strategic National Stockpile of drugs and medical supplies, managed by the CDC.
The BARDA stockpile contains vaccines based on four different H5N1 strains, dating from 2004 to 2009; one H7N9 strain; and two adjuvants, he said. The supply includes more than 200 million doses of H5N1 vaccine.
Most of the stockpile is stored in bulk form rather than in vials. "The reason we do that is we don't have the problem of expiration dating," Robinson said.
He said the vaccines are monitored for potency and immunogenicity. "Even some of the earliest vaccine we had made back in 2005 still is potent, and we actually have done a number of studies that show that not only are they potent but also they're immunogenic."
"Every day is a new record, because influenza vaccines have never been kept this long," he said.
However, he commented, "If we have to update those because of lack of potency we certainly will."
Pandemic flu funding
On budget matters, Robinson noted that BARDA's fiscal 2015 budget request for pandemic flu was $168 million, but only $72 million was provided. For 2016, which begins in October, the request is again for $168 million, but the agency may again be shortchanged. Bills in the House and Senate would keep the funding flat at $72 million, according to analysts with the Trust for America's Health, a nonprofit public health advocacy group.
Robinson explained that BARDA doesn't depend solely on annual appropriations for its pandemic flu program; it also has some money left over from the 2009 supplemental appropriation for the H1N1 flu pandemic.
"This year we'll probably be spending $240 to $260 million between the annual budget and unobligated balances," he said. "In 2016, from what we know, well probably deplete the unobligated balances from that supplemental appropriation."
In addition, the agency has some leftover money from earlier projects that were terminated, he said. For example, he noted that BARDA had contracts with six companies to develop cell-based flu vaccines, but three of those eventually dropped out, which left some funds unspent.
"Am I concerned that we're going to have to prioritize our investments in stockpiling and building facilities?" Robinson said. "I'm very concerned about it, but it's not as bleak as 'We have only $72 million.' So far we haven't had to turn down a project we wanted to do."
Jan 27 BARDA RFP for advanced development of universal flu vaccines