The Effect of Preexisting Immunity on Virus Detection and Immune Responses in a Phase II, Randomized Trial of a Russian-Backbone, Live, Attenuated Influenza Vaccine in Bangladeshi Children

Elizabeth B. Brickley, Peter F. Wright, Alexey Khalenkov, Kathleen M. Neuzil, Justin R. Ortiz, Larisa Rudenko, Min Z. Levine, Jacqueline M. Katz, W Abdullah Brooks

Research output: Contribution to journalArticle

Abstract

Background: In a 2012 Phase II clinical trial, 300 Bangladeshi children aged 24 to 59 months with no prior influenza vaccine exposure were randomized to receive a single intranasally-administered dose of either trivalent, Russian-backbone, live, attenuated influenza vaccine (LAIV) or placebo. Protocol-defined analyses, presented in the companion manuscript, demonstrate decreased viral detection and immunogenicity for A/H1N1pdm09, relative to the A/H3N2 and B strains. This post hoc analysis of the trial data aims to investigate the LAIV strain differences by testing the hypothesis that preexisting humoral and mucosal immunity may influence viral recovery and immune responses after LAIV receipt. Methods: We used logistic regressions to evaluate the relations between markers of preexisting immunity (ie, hemagglutination inhibition [HAI], microneutralization, and immunoglobulin G and immunoglobulin A (both serum and mucosal antibodies) and LAIV viral recovery in the week post-vaccination. We then tested for potential effect modification by baseline HAI titers (ie, <10 versus ≥10) and week 1 viral recovery on the LAIV-induced serum and mucosal immune responses, measured between days 0 and 21 post-vaccination. Results: Higher levels of preexisting immunity to influenza A/H3N2 and B were strongly associated with strain-specific prevention of viral shedding upon LAIV receipt. While evidence of LAIV immunogenicity was observed for all 3 strains, the magnitudes of immune responses were most pronounced in children with no evidence of preexisting HAI and in those with detectable virus. Conclusions: The results provide evidence for a bidirectional association between viral replication and immunity, and underscore the importance of accounting for preexisting immunity when evaluating virologic and immunologic responses to LAIVs. Clinical Trials Registration: NCT01625689.

Original languageEnglish (US)
Article numberciy1004
Pages (from-to)786-794
Number of pages9
JournalClinical Infectious Diseases
Volume69
Issue number5
DOIs
StatePublished - Aug 16 2019

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Attenuated Vaccines
Influenza Vaccines
Immunity
Viruses
Hemagglutination
Mucosal Immunity
Vaccination
Virus Shedding
Phase II Clinical Trials
Manuscripts
Humoral Immunity
Serum
Immunoglobulin A
Human Influenza
Immunoglobulin G
Logistic Models
Placebos
Clinical Trials
Antibodies

Keywords

  • humoral immunity
  • immunogenicity
  • influenza vaccine
  • mucosal immunity

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases

Cite this

The Effect of Preexisting Immunity on Virus Detection and Immune Responses in a Phase II, Randomized Trial of a Russian-Backbone, Live, Attenuated Influenza Vaccine in Bangladeshi Children. / Brickley, Elizabeth B.; Wright, Peter F.; Khalenkov, Alexey; Neuzil, Kathleen M.; Ortiz, Justin R.; Rudenko, Larisa; Levine, Min Z.; Katz, Jacqueline M.; Brooks, W Abdullah.

In: Clinical Infectious Diseases, Vol. 69, No. 5, ciy1004, 16.08.2019, p. 786-794.

Research output: Contribution to journalArticle

Brickley, Elizabeth B. ; Wright, Peter F. ; Khalenkov, Alexey ; Neuzil, Kathleen M. ; Ortiz, Justin R. ; Rudenko, Larisa ; Levine, Min Z. ; Katz, Jacqueline M. ; Brooks, W Abdullah. / The Effect of Preexisting Immunity on Virus Detection and Immune Responses in a Phase II, Randomized Trial of a Russian-Backbone, Live, Attenuated Influenza Vaccine in Bangladeshi Children. In: Clinical Infectious Diseases. 2019 ; Vol. 69, No. 5. pp. 786-794.
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AU - Brickley, Elizabeth B.

AU - Wright, Peter F.

AU - Khalenkov, Alexey

AU - Neuzil, Kathleen M.

AU - Ortiz, Justin R.

AU - Rudenko, Larisa

AU - Levine, Min Z.

AU - Katz, Jacqueline M.

AU - Brooks, W Abdullah

PY - 2019/8/16

Y1 - 2019/8/16

N2 - Background: In a 2012 Phase II clinical trial, 300 Bangladeshi children aged 24 to 59 months with no prior influenza vaccine exposure were randomized to receive a single intranasally-administered dose of either trivalent, Russian-backbone, live, attenuated influenza vaccine (LAIV) or placebo. Protocol-defined analyses, presented in the companion manuscript, demonstrate decreased viral detection and immunogenicity for A/H1N1pdm09, relative to the A/H3N2 and B strains. This post hoc analysis of the trial data aims to investigate the LAIV strain differences by testing the hypothesis that preexisting humoral and mucosal immunity may influence viral recovery and immune responses after LAIV receipt. Methods: We used logistic regressions to evaluate the relations between markers of preexisting immunity (ie, hemagglutination inhibition [HAI], microneutralization, and immunoglobulin G and immunoglobulin A (both serum and mucosal antibodies) and LAIV viral recovery in the week post-vaccination. We then tested for potential effect modification by baseline HAI titers (ie, <10 versus ≥10) and week 1 viral recovery on the LAIV-induced serum and mucosal immune responses, measured between days 0 and 21 post-vaccination. Results: Higher levels of preexisting immunity to influenza A/H3N2 and B were strongly associated with strain-specific prevention of viral shedding upon LAIV receipt. While evidence of LAIV immunogenicity was observed for all 3 strains, the magnitudes of immune responses were most pronounced in children with no evidence of preexisting HAI and in those with detectable virus. Conclusions: The results provide evidence for a bidirectional association between viral replication and immunity, and underscore the importance of accounting for preexisting immunity when evaluating virologic and immunologic responses to LAIVs. Clinical Trials Registration: NCT01625689.

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