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Previous Volume 359:1631-1633 October 9, 2008 Number 15 Next

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To the Editor: Antigenically distinct avian influenza A (H5N1) viruses are widely dispersed.¹ Clade 1 H5N1 viruses previously predominated in Indochina. Indonesian, Eurasian, and African viruses are clustered in a clade 2 group, with antigenically distinct sublineages. Clade 0 viruses caused influenza outbreaks in Hong Kong in 1997 but have not been isolated since then. To reduce shortfalls in vaccine supply at the onset of the next pandemic, advance stockpiling of vaccine has been suggested. Because of antigenic evolution of H5N1, current vaccines may be suboptimally matched to the actual pandemic virus. Proactive priming may induce immune memory, allowing low-dose vaccination to induce rapid cross-protection when needed.

We report on an open-label study conducted from June through August 2007 at Leicester Royal Infirmary, Leicester, United Kingdom (for details, see the Supplementary Appendix, available with the full text of this letter at www.nejm.org). Two 7.5-µg doses of MF59-adjuvanted, surface-antigen vaccine against clade 1 A/Vietnam/1194/2004 (NIBRG-14) (Novartis) were administered by intramuscular injection 21 days apart to subjects who had been vaccinated (primed) with clade 0 H5 vaccine at least 6 years earlier. All primed subjects had received two doses of either MF59-adjuvanted or nonadjuvanted (plain) A/duck/Singapore/97 (H5N3) vaccine containing 7.5 to 30 µg of hemagglutinin in studies conducted between 1999 and 2001.^2,3,4 Some subjects had also received a booster dose 16 months after primary immunization.³ Antibody responses were detected with the use of neutralizing and hemagglutination-inhibition assays performed at the U.K. Health Protection Agency, with homologous clade 1 NIBRG-14 and heterologous clade 2.2 NIBRG-23 vaccine reference strains and by hemagglutination-inhibition assay at the Centers for Disease Control and Prevention with wild-type A/Vietnam/1194/2004 (clade 1), A/Indonesia/5/2005 (clade 2.1), A/Anhui/1/2005 (clade 2.3), and A/Turkey/15/2006 (clade 2.2) viruses (see the Supplementary Appendix for details).

Twenty-four subjects had received two or three doses of either plain or MF59-adjuvanted H5N3 vaccine, with subjects equally divided between the two groups. Thirty subjects were unprimed. Vaccines had acceptable side-effect profiles, and no serious vaccine-related adverse events were recorded. Serum samples were obtained immediately before each of the two doses of vaccine was administered (on days 0 and 21) and on days 7, 14, and 42 after vaccination.

On each post-vaccination day, and with each assay, geometric mean titers of antibodies to NIBRG-14 and NIBRG-23 were significantly higher among the primed subjects than among the unprimed subjects (P<0.001 for all comparisons, except on day 42 for NIBRG-14 on hemagglutination-inhibition assay). From day 14 onward, and for each assay, titers of antibodies to both viruses were significantly higher in the MF59-primed group than in the plain-primed group (P<0.05 for all comparisons). The highest titers were observed on day 14 in the MF59-primed group, with geometric mean titers of antibodies to NIBRG-14 and NIBRG-23 of 1:378 and 1:347, respectively, on hemagglutination-inhibition assay and of 1:1754 and 1:2128, respectively, on neutralizing assay (Figure 1 and the Supplementary Appendix). No relation between the post-vaccination titer and the number of previous doses of H5N3 vaccine or their antigen content was observed. By day 7, at least 80% of MF59-primed subjects had titers of at least 1:40 for all wild-type viruses tested on hemagglutination-inhibition assay.

View larger version (32K): [in this window] [in a new window]   Figure 1. Titers of Antibodies to NIBRG-14 and NIBRG-23 and Reverse Cumulative Distribution Curves on Day 7 after One Dose of Vaccine. Shown are geometric mean (log10) titers (GMT) of antibodies to A/Vietnam/1194/2004 (NIBRG-14) (Panel A) and A/turkey/Turkey/1/2005 (NIBRG-23) (Panel B), as determined by hemagglutination-inhibition (HAI) assay, after the administration of two doses of vaccine 21 days apart. Responses are shown for 30 subjects who had not previously received H5 influenza vaccine (unprimed subjects), 12 subjects who had been primed with nonadjuvanted (plain) H5 vaccine, and 12 subjects who had been primed with MF59-adjuvanted H5 vaccine. Reverse cumulative distribution curves at day 7 after one dose of vaccine are shown for subjects who had been primed with either MF59-adjuvanted H5 vaccine (Panel C) or plain H5 vaccine (Panel D). The percentage of subjects with an HAI titer is based on the total number of samples available. Antibody titers are shown for four wild-type H5 viruses: A/Vietnam/1194/2004, A/Indonesia/5/2005, A/Anhui/1/2005, and A/Turkey/15/2006. Ind denotes Indonesia, and VN Vietnam.

 
Modeling of pandemic spread shows that the maximum reduction in viral transmission is achieved by the induction of a response within 2 weeks after the outbreak of the pandemic.⁵ Because two doses of the vaccine are required, rapid vaccine deployment will be challenging. Our findings indicate that priming subjects with H5 antigen induces a rapidly mobilized, long-lasting immune memory after the administration of low-dose, antigenically distinct vaccine. Given the protective titers detected by day 7, the effect of MF59 adjuvant is striking. Consideration could be given to a proactive vaccine-priming strategy, particularly among those at high risk for pandemic influenza such as health care workers, so that cross-clade antibodies could be rapidly generated after single vaccination or after exposure to the pandemic virus.

Iain Stephenson, M.A., F.R.C.P.
Karl G. Nicholson, F.R.C.Path., F.R.C.P.
University Hospitals Leicester
Leicester LE1 5WW, United Kingdom
iain.stephenson{at}uhl-tr.nhs.uk

Katja Hoschler, Ph.D.
Maria C. Zambon, Ph.D.
Health Protection Agency
Colindale NW9 5HT, United Kingdom

Kathy Hancock, Ph.D.
Joshua DeVos, M.P.H.
Jacqueline M. Katz, Ph.D.
Centers for Disease Control and Prevention
Atlanta, GA 30333

Michaela Praus
Angelika Banzhoff, M.D.
Novartis Vaccine
35041 Marburg, Germany

Dr. Stephenson reports receiving consulting and lecture fees and grant support from Hoffmann–La Roche and Novartis; Dr. Nicholson, receiving consulting and lecture fees from GlaxoSmithKline and Novartis; Dr. Zambon, receiving grant support from CSL, Sanofi-Pasteur, Baxter, and Novartis; Dr. Hancock, receiving grant support from Juvaris BioTherapeutics and the Biomedical Advanced Research and Development Authority; Dr. Katz, receiving grant support from NexBio and Nobilon; and Ms. Praus and Dr. Banzhoff, being employees of Novartis. No other potential conflict of interest relevant to this letter was reported.

References

1. Chen H, Smith GJ, Li KS, et al. Establishment of multiple sublineages of H5N1 influenza virus in Asia: implications for pandemic control. Proc Natl Acad Sci U S A 2006;103:2845-2850. [Free Full Text]
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;357:1937-1943. [CrossRef][Web of Science][Medline]
3. Stephenson I, Nicholson KG, Colegate A, et al. Boosting immunity to influenza H5N1 with MF59-adjuvanted H5N3 A/Duck/Singapore/97 vaccine in a primed human population. Vaccine 2003;21:1687-1693. [CrossRef][Web of Science][Medline]
4. Stephenson I, Zambon MC, Rudin A, et al. Phase I evaluation of intranasal trivalent inactivated influenza vaccine with nontoxigenic Escherichia coli enterotoxin and novel biovector as mucosal adjuvants, using adult volunteers. J Virol 2006;80:4962-4970. [Free Full Text]
5. Ferguson NM, Cummings DAT, Fraser C, Cajka JC, Cooley PC, Burke DS. Strategies for mitigating an influenza pandemic. Nature 2006;442:448-452. [CrossRef][Web of Science][Medline]

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