Clinical Pharmacokinetics

, Volume 36, Supplement 1, pp 51–58 | Cite as

Coadministration of Orally Inhaled Zanamivir with Inactivated Trivalent Influenza Vaccine Does Not Adversely Affect the Production of Antihaemagglutinin Antibodies in the Serum of Healthy Volunteers

  • Alison Webster
  • Malcolm Boyce
  • Sally Edmundson
  • Irene Miller
Original Research Article

Abstract

Objective

Zanamivir, a clinically proven potent and specific inhibitor of influenza A and B neuraminidase, has been approved in some countries for the treatment of influenza and is in late-stage development for the prophylaxis of influenza. This study investigated whether the coadministration of zanamivir and influenza vaccine affected the development of antibody responses to injected influenza haemagglutinin.

Design

This double-blind randomised placebo-controlled study compared the antihaemagglutinin antibody production [haemagglutination inhibition (HAI) titre] after administration of inactivated trivalent influenza vaccine in healthy volunteers receiving zanamivir or placebo once daily for 28 days.

Study participants

138 healthy volunteers (52 men and 86 nonpregnant women, mean age 32.7 years) were randomised to the zanamivir (70 participants) or placebo (68 participants) groups.

Interventions

Participants received a single intramuscular dose (deltoid muscle) of the 1997/1998 trivalent inactivated influenza vaccine (surface antigen) PhEur (Fluvirin™) on day 1, and were then randomised to receive zanamivir 10 mg/day by oral inhalation or placebo for 28 days. Serum samples for determination of HAI titres were obtained before vaccination and on days 15 and 29. Compliance, adverse events and laboratory parameters were monitored.

Results

The primary measure of response was the geometric mean increase in HAI titre against the 3 viral antigens contained in the vaccine, calculated as the ratio of the value 4 weeks after vaccination to the baseline value. The means (and 2-sided 95% confidence intervals) for the ratio between the geometric mean increase with placebo and the increase with zanamivir were as follows: 1.1 (0.7, 1.5) for influenza B, 0.7 (0.4, 1.2) for influenza A H1N1, and 0.6 (0.4, 1.1) for influenza AH3N2. (This corresponds to a test level of α = 0.025 for the hypothesis that the increase with placebo was ≥ 2-fold greater than the increase with zanamivir.) Alack of effect was concluded as values of 2.0 or greater (i.e. a 2-fold difference) were excluded. Comparisons were also made of the increase in titre at 2 weeks, the proportions of participants with at least a 4-fold increase in titre and the proportions of participants with a titre of at least 1: 40. These comparisons revealed no differences between zanamivir- and placebo-treated groups. The nature and incidence of adverse events observed with zanamivir were similar to those observed with placebo.

Conclusions

Overall, zanamivir was not associated with a reduced response in HAI titre against the 3 vaccine antigens when compared with placebo. In addition, zanamivir was well tolerated. Inhaled zanamivir 10mg once daily has been demonstrated to prevent symptomatic laboratory-confirmed influenza in a community outbreak. Zanamivir should have the potential to provide protection during the 2- to 4-week period before full immunity is induced, following vaccination at a time when influenza is circulating in the community.

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References

  1. 1.
    Douglas RG. Prophylaxis and treatment of influenza. N Engl J Med 1990; 322: 443–50.PubMedCrossRefGoogle Scholar
  2. 2.
    Hobson D, Curry RC, Beave AS, et al. Haemagglutination inhibition antibody titres as a measure of protection against influenza in man. Dev Biol Stand 1973; 20: 164–8.Google Scholar
  3. 3.
    La Montagne JR, Noble GR, Quinnan GV, et al. Summary of clinical trials of inactivated influenza vaccine — 1978. Rev Infect Dis 1983; 5: 723–36.PubMedCrossRefGoogle Scholar
  4. 4.
    Cate TR, Couch RB, Parker D, et al. Reactogenicity, immunogenicity and antibody persistence in adults given inactivated influenza virus vaccines — 1978. Rev Infect Dis 1983; 5: 737–47.PubMedCrossRefGoogle Scholar
  5. 5.
    Potter CW, Oxford JS. Determinants of immunity to influenza infection in man. Br Med Bull 1979; 35: 69–75.PubMedGoogle Scholar
  6. 6.
    Advisory Committee on Immunization Practices (ACIP). Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 1998; 47(RR-6): 1–26.Google Scholar
  7. 7.
    Woods JM, Bethell RC, Coates JAV, et al. 4-Guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid is a highly effective inhibitor of both the sialidase (neuraminidase) and of growth of a wide range of influenza A and B viruses in vitro. Antimicrob Agents Chemother 1993; 37: 1473–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Von Itzstein M, Wu WY, Kok GB, et al. Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature 1993; 363: 418–23.CrossRefGoogle Scholar
  9. 9.
    Hayden FG, Osterhaus AD, Treanor JJ, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza viras infections. N Engl J Med 1997; 337: 874–80.PubMedCrossRefGoogle Scholar
  10. 10.
    Silagy CA, Campion KJ, Keene O. The efficacy and safety of zanamivir in the treatment of influenza in otherwise healthy and ‘high risk’ individuals [abstract no. H-56]. Abstracts of the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1998 Sep 24–28; San Diego, CA: 331.Google Scholar
  11. 11.
    Fleming D, Makela M, Pauksens K, et al. ‘High risk’ and otherwise healthy patients demonstrate alleviation of influenza symptoms 2.5 days earlier following inhaled zanamivir treatment; European Study, winter 1997/8. Abstracts of the 36th Annual Meeting of the Infectious Disease Society of America; 1998 Nov 12–15; Denver, Co; 1998: 249.Google Scholar
  12. 12.
    Monto AS, Robinson DP, Herlocher ML, et al. Safety and efficacy of the neuraminidase inhibitor zanamivir in prevention of influenza among healthy adults. JAMA. In press.Google Scholar
  13. 13.
    Jones B, Jarvis P, Lewis JA, et al. Trials to assess equivalence: the importance of rigorous methods. BMJ 1996; 313: 550.Google Scholar
  14. 14.
    Monto AS, Maassab HF. Ether treatment of type B influenza virus antigen for the hemagglutinin inhibition test. J Clin Microbiol 1981; 13: 54–7.PubMedGoogle Scholar
  15. 15.
    Committee for Proprietary Medicinal Products. Note for guidance on harmonisation of requirements for influenza vaccine. The European Agency for the Evaluation of Medicinal Products, Human Medicines Evaluation Unit; 1997 Mar 12: CPMP/BWP/214/96.Google Scholar
  16. 16.
    Hayden FG. Antivirais for pandemic influenza. J Infect Dis 1997; 176 Suppl. 1: S56–61.PubMedCrossRefGoogle Scholar
  17. 17.
    Hayden FG. Amantadine and rimantadine resistance in influenza A viruses. Curr Opin Infect Dis 1994; 7: 674–7.CrossRefGoogle Scholar
  18. 18.
    Belshe RB, Burk, Newman F, et al. Resistance of influenza A virus to amantadine and rimantadine: results of one decade of surveillance. J Infect Dis 1989; 159(3): 430–5.PubMedCrossRefGoogle Scholar
  19. 19.
    Osterhaus ADME, Tisdale M, Elliot M. A double-blind, randomised trial of zanamivir in the treatment of acute influenza — clinical and virological efficacy results [abstract H-67]. Final Program, Abstracts and Exhibits Addendum; 38th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1998 Sep 24–28; San Diego, CA: 11.Google Scholar
  20. 20.
    Barnett J, Dempsey M, Tisdale M, et al. Susceptibility monitoring of influenza virus clinical isolates to the neuraminidase inhibitor zanamivir (GG167) during phase II clinical efficacy trials. Abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1; Toronto, Canada: 230.Google Scholar

Copyright information

© Adis International Limited 1999

Authors and Affiliations

  • Alison Webster
    • 1
  • Malcolm Boyce
    • 2
  • Sally Edmundson
    • 1
  • Irene Miller
    • 1
  1. 1.Glaxo Wellcome Research and DevelopmentGreenford, MiddlesexEngland
  2. 2.Hammersmith Medicines Research LtdLondonEngland

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