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Holding the Government Accountable

Recombinant Vaccine for Pandemic Flu: Why Is It Not in Large‑scale Production?

An unusual, thoroughly tested, safe and effective type of vaccine – "recombinant vaccine" – can be produced much more quickly than the customary vaccines. But faulty government planning in past years delayed the production of this vaccine. Thus recombinant vaccine will not be ready in large amounts in time to battle the spread of H1N1 swine flu, certainly not during the next few months.

We believe that, if there had been an appropriate sense of urgency and adequate government funding, many doses of recombinant vaccine – perhaps tens of millions of doses – would be available at present. Large-scale nationwide vaccinations would now be taking place.

Most Americans who are vaccinated during the next few months will receive H1N1 swine flu vaccine made in chicken eggs. A different type of influenza vaccine, recombinant vaccine, is made in non‑mammalian cell culture and is composed largely of one component (purified hemagglutinin) of the particular strain of influenza. With the isolation of virus from a patient as the starting point, the production of recombinant flu vaccine in large amounts takes half as long (more or less) as the six‑month period needed for egg‑based vaccines.

For more than ten years, recombinant flu vaccine has been recognized as a promising means of protection, particularly at the start of a pandemic when a novel strain of influenza appears.1 This method of producing vaccine is fast, and it can be expanded quickly from laboratory to pilot plant to large-scale production in multiple locations. Research on several recombinant vaccines, including vaccines for influenza, has been well supported by the NIH, especially by the National Institute of Allergy and Infectious Diseases (NIAID). Clinical studies have confirmed the safety and effectiveness of a recombinant vaccine for seasonal influenza.

However, the success of this research did not lead quickly, as it should have, to specific plans for industrial‑scale production of recombinant vaccine in the event of a pandemic. Elsewhere we have described a series of governmental delays and omissions.2 These seem to reflect, at the very least, a lack of a sense of urgency within DHHS. Specifically, two years ago DHHS solicited proposals for the production of recombinant flu vaccine for use in a pandemic. The Request for Proposals was issued in October 2007 instead of several years earlier – a significant and damaging delay – and the process of awarding the contract resulted in further delays.3 A contract was finally awarded in June 2009.

The recipient of the contract award, Protein Sciences Corp., has the capability of preparing large amounts of recombinant H1N1 flu vaccine quickly.4 The method used to make this vaccine is the same as that used for the company's seasonal flu vaccine, which has already undergone extensive and successful clinical testing.

Unfortunately, it may be too late for large amounts of recombinant flu vaccine to be produced in time for the expected peak incidence of H1N1 flu in the next few months. However, a decline in the frequency of illness this winter may be followed by a resurgence of H1N1 flu next year; this has happened in past pandemics. Officials in DHHS, non-government experts, and others should consider whether emergency government support (both financial and regulatory) is warranted for the fast‑track, large‑scale production and administration of recombinant flu vaccine.5

More than ten years ago, when a batch of a special flu vaccine was needed in a hurry, senior officials in DHHS recognized the clear superiority of the recombinant vaccine. On December 7, 1997, Protein Sciences received an "urgent call" from an NIH official requesting quick production of vaccine for a small outbreak of human H5N1 avian influenza in Hong Kong.6 Eight weeks later (which is much less than six months later!), recombinant vaccine, produced under a contract with DHHS, was ready for administration to chickens and soon afterwards to humans.7 Over 200 healthcare workers and researchers were vaccinated. As noted in a report on these clinical observations in the journal Vaccine, the recombinant vaccine was ready "before any other vaccine candidates were available for human trials."8

During this episode over a decade ago, in December 1997, senior officials in DHHS put their special knowledge to good use when they chose a recombinant vaccine to deal quickly with an outbreak of flu. It is unfortunate and puzzling that they didn't act on that knowledge long before October 2007 when they finally issued the Request for Proposals, which (after additional delays) led in June 2009 to the contract for recombinant vaccine production.

1 Lakey, David L, et al. "Recombinant baculovirus influenza A hemagglutinin vaccines are well tolerated and immunogenic in healthy adults." J. Infectious Diseases, vol. 174. October 1996. pp. 838-841.

Johansson, Bert E. "Immunization with influenza A virus hemagglutinin and neuraminidase produced in recombinant baculovirus results in a balanced and broadened immune response superior to conventional vaccine." Vaccine, vol. 17, April 1999. pp. 2073-2080.

Treanor, John J., et al. "Safety and Immunogenicity of a Baculovirus-Expressed Hemagglutinin Influenza Vaccine: A Randomized Controlled Trial." J. American Medical Association, vol 297. April 11, 2007, pp. 1577-1582.

2 The delays and omissions are discussed in the July 20, 2009. online commentary, "Flu Vaccine Shortage? The Whole Truth, Please."

3 As noted in a previous footnote, by October 2007, when the Request for Proposals was issued, the scientific literature contained many reports on recombinant flu vaccines by several independent research groups. By then, the recombinant technology was well known to produce a safe, effective and economical flu vaccine – one that was superior in several ways to the conventional technology (superior in its quick start, fast scale-up, and large-scale production). The virus (baculovirus, an insect virus) can be grown on a large scale under biosafety containment requirements less rigorous than those required for human viruses. This frees up the manufacturing facilities that are ordinarily used to prepare vaccine for seasonal flu by the customary methods.

4 FluBlok, the vaccine made by Protein Sciences, is under review by the FDA for product approval. Vaccines made by other companies (Novavax, Vaxinnate) have some of the same advantages as the Protein Sciences vaccine. However, both are in much earlier stages of clinical testing.

5 If cases of H1N1 flu occur in the fall or winter of 2010, there will presumably be plenty of egg‑based vaccine by then. The recombinant H1N1 vaccine would be useful in the somewhat unlikely event that the flu virus hemagglutinin at that time is sufficiently different antigenically from the original hemagglutinin. However, that unlikely event may occur. In that case the rapid startup and other features of the method for producing recombinant vaccine would be useful. Moreover, the facilities and expertise for production of recombinant vaccine will be invaluable whenever a newly emerging virus like SARS begins to spread.

6 "Emergency Human Vaccine Against Hong Kong H5N1 Influenza 'Bird Flu' Developed." Vaccine Weekly or NewsRx, February 16, 1998. From this article: "When recent cases of H5N1 influenza infections in humans were reported from Hong Kong, officials from the NIH requested that Protein Sciences escalate its efforts to produce a vaccine. Dr. Gale Smith, Protein Sciences, said, 'In an urgent call on Sunday, December 7, [1997], an NIH official informed us of two new cases of H5N1 influenza in Hong Kong. We immediately began an all-out effort to produce a vaccine'" A partial version of the article is available at with a link to a paid version of the full article.

7 Manon M. J. Cox. "Pandemic Influenza: Overview of Vaccines and Antiviral Drugs." Yale Journal of Biology and Medicine, Vol. 79, 2005. pp. 317-324.

8 John J. Treanor, et al. “Safety and immunogenicity of a recombinant hemagglutinin vaccine for H5 influenza in humans.” Vaccine, Vol. 19, Feb. 8, 2001. pp. 1732-1737.