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Update on Strategies to Develop Pandemic Influenza Vaccines

By Luciana Borio, M.D. and Richard Waldhorn, M.D., February 14, 2006


The recent epizootics of highly pathogenic avian influenza (HPAI) and associated human infections have prompted the U.S. government to begin preparations for a possible pandemic. Since vaccination is the best means by which to contain the spread of a pandemic virus, the development of inactivated and live attenuated vaccines is central to the government’s efforts. Several clinical trials now underway are testing the safety and efficacy of vaccine candidates. While not a comprehensive review, the following brief summary of information presented in Washington, DC, at the meeting, “Seasonal & Pandemic Influenza 2006,” (Jan. 31 to Feb. 2, 2006, sponsored by IDSA, CDC, NIAID, and SHEA) does provide an update on current developments.

Influenza A Viruses

Influenza A, which infects a wide variety of birds and mammals, is one of four genera in the family Orthomyxoviridae [1]. The viruses are classified on the basis of the antigenicity of their surface glycoproteins, hemagglutinin (HA), and neuraminidase (NA). There are 16 known HA and 9 NA subtypes. Only influenza A viruses of the H1, H2, and H3 HA and of the N1 and N2 NA subtypes have circulated among humans in the 20th century. At present, seasonal epidemics are caused by H3N2 and H1N1 influenza A viruses and influenza B viruses. Pandemics are caused by the emergence of a novel HA, with or without a novel NA subtype, to which humans have little or no immunity. While it is not possible to predict when the next pandemic will occur, the unprecedented epizootic of highly pathogenic H5N1 avian influenza in birds since 2003 and the associated human cases have heightened the alert that the next pandemic may be brewing.

Challenges to Pandemic Vaccine Development

Successful development of a pandemic vaccine must still overcome several challenges:

  • H5 HA is poorly immunogenic as compared with strains of H3N2 or H1N1 viruses. To date, vaccines against H5 viral subtypes have required 2 doses or an adjuvant to induce the necessary level of neutralizing antibodies [2, 3]. Neutralizing antibodies against the HA are critical for protection against infection (cellular immunity assists with viral clearance).

  • Influenza viruses evolve continuously. There are already two clades of HPAI H5N1 viruses circulating [4]. Thus, vaccines produced today may be poorly matched to the eventual circulating pandemic virus.

  • Manufacturing capacity is limited, and licensing requirements are stringent. Biological safety containment of vaccine seed viruses is required.

Principal Ongoing Strategies for Pandemic Vaccine Development

Although the next pandemic could possibly be caused by a virus other than the H5N1 virus now circulating in much of Asia, most vaccine development effort has been focused on H5N1 HPAI. The U.S. DHHS has the goal of maintaining a pre-pandemic vaccine stockpile adequate for 20 million persons in the critical workforce and high priority groups. To this end, DHHS has contracted with sanofi pasteur to bulk produce ~5.83 M doses of vaccine with 90 µg of HA antigen/dose and with Chiron to bulk produce ~2.0 M doses of the same, by the end of this month [5].

Research has focused on the production of inactivated influenza vaccine candidates, both with and without adjuvants, and live attenuated influenza A vaccine candidates, as described below.

  • Inactivated vaccine candidates: An unadjuvanted, inactivated H5N1 vaccine candidate has been manufactured by sanofi pasteur (Swiftwater, PA). Prospective, randomized, double-blind clinical trials with approximately 450 healthy adults, aged 18-64, established the need for two doses of 90 µg each to elicit serum antibody response of a magnitude similar to that of the licensed seasonal vaccine (defined as neutralizing titer of 1:40). The licensed seasonal vaccine contains only 15 µg of antigen per dose. The vaccine was well tolerated in trials, but vaccinees did show a dose-related increase in pain and tenderness at the vaccination site [6]. The same vaccine is now being evaluated in healthy elderly people and children. The addition of alum adjuvant to this vaccine candidate has reportedly shown a modest effect of 50% enhancement, at best, with respect to immunogenicity in healthy adults [7]. An alternative adjuvant, MF59, produced by Chiron Corporation (Emeryville, CA), is being evaluated in phase 1 clinical trials employing an H9N2 vaccine candidate.

  • Live, attenuated vaccine candidates: Live, attenuated vaccines against pandemic influenza might require fewer doses and provide broader and more rapid immunity. Intranasally administered vaccine induces mucosal and systemic immunity, restricting viral replication in the upper and lower respiratory tracts, respectively. In addition, they induce humoral and cellular immunity. A seasonal vaccine is already licensed in the U.S. under the trade name FluMist (MedImmune, Inc., Gaithersburg, MD). The risk for reassortment of the vaccine virus with a circulating influenza virus, resulting in a novel viral subtype that could spread, is a concern with this technique.Under a contract with the U.S. government, MedImmune will develop at least one vaccine for each of the 16 variations of a key influenza surface protein hemagglutinin. Candidate vaccines have been generated for H5 and H9 subtypes, and H5 candidates are undergoing preclinical testing, whereas the H9 candidate has now entered phase 1 clinical trials [8]. Strategies to augment immunogenicity, such as alternative routes of administration (e.g., intradermal instead of intramuscular) or priming the population to a novel HA prior to a pandemic, are also being studied or considered.


There are several pandemic influenza vaccine candidates currently under development. Most information on the various clinical trials conducted by NIAID has not yet been made publicly available, and, to date, most clinical studies have yielded disappointing results with respect to immunogenicity. Given the magnitude of the threat posed by pandemic avian influenza, many vaccine strategies should be evaluated concurrently.


  1. Treanor JJ. Influenza virus. In: Mandell GL, Douglas RG, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 5th ed. Philadelphia: Elsevier Churchill Livingstone; 2000: Chapter 153;1823.
  2. Nicholson KG, Colegate AE, Podda A, et al. Safety and antigenicity of non-adjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a randomised trial of two potential vaccines against H5N1 influenza. Lancet 2001;357(9272):1937-43.
  3. Treanor JJ, Wilkinson BE, Masseoud F, et al. Safety and immunogenicity of a recombinant hemagglutinin vaccine for H5 influenza in humans. Vaccine 2001;19(13-14):1732-7.
  4. The World Health Organization Global Influenza Program Surveillance Network. Evolution of H5N1 avian influenza viruses in Asia. Emerg Infect Dis 2005;11(10). Available at: Accessed February 10, 2006.
  5. Robinson R. HHS Influenza Vaccine Projects for NVAC Meeting [PowerPoint presentation]. Washington, DC: Department of Health and Human Services; November 29-30, 2005. Available at: Accessed February 10, 2006.
  6. Treanor J. H5N1 clinical Trials, sanofi pasteur [PowerPoint presentation].
  7. Borio L. Personal communication with John J. Treanor, University of Rochester, February 3, 2006.
  8. Karron R. Phase I Inpatient Evaluation of a Live Attenuated H9N2 ca Reassortant Vaccine in Healthy Adults Born After 1968 [PowerPoint presentation]. Baltimore: Center for Immunization Research, Bloomberg School of Public Health, Johns Hopkins University.