Prime-boost interval matters: a randomized phase 1 study to identify the minimum interval necessary to observe the H5 DNA influenza vaccine priming effect

Abstract

Background: H5 DNA priming was previously shown to improve the antibody response to influenza A(H5N1) monovalent inactivated vaccine (MIV) among individuals for whom there was a 24-week interval between prime and boost receipt. This study defines the shortest prime-boost interval associated with an improved response to MIV.

Methods: We administered H5 DNA followed by MIV at intervals of 4, 8, 12, 16, or 24 weeks and compared responses to that of 2 doses of MIV (prime-boost interval, 24 weeks).

Results: H5 DNA priming with an MIV boost ≥12 weeks later showed an improved response, with a positive hemagglutination inhibition (HAI) titer in 91% of recipients (geometric mean titer [GMT], 141-206), compared with 55%-70% of recipients with an H5 DNA and MIV prime-boost interval of ≤8 weeks (GMT, 51-70) and 44% with an MIV-MIV prime-boost interval of 24 weeks (GMT, 27).

Conclusion: H5 DNA priming enhances antibody responses after an MIV boost when the prime-boost interval is 12-24 weeks. Clinical Trials Registration. NCT01086657.

Keywords: Avian influenza; DNA vaccine; H5N1; boost interval; hemagglutination inhibition.

Figure 1.

Antibody responses elicited by prime-boost vaccination with influenza H5N1 monovalent inactivated vaccine (MIV) on day 0 and at week 24 (group 1), H5 DNA on day 0 and MIV at week 4 (group 2), H5 DNA on day 0 and MIV at week 8 (group 3), H5 DNA on day 0 and MIV at week 12 (group 4), H5 DNA on day 0 and MIV at week 16 (group 5), and H5 DNA on day 0 and MIV at week 24 (group 6). A–C, Mean (±standard error of the mean) enzyme-linked immunosorbent assay (ELISA) end point titer (A), hemagglutination inhibition (HAI) titer (B), and 80% inhibition serum (ID₈₀) neutralizing antibody (NAb) titer (C) 2 weeks after MIV boosting. P values are shown for statistically significant differences. D, Stem-directed antibody responses after MIV boosting. Postvaccination sera were preabsorbed with 293A cells expressing the stem mutant (Δstem) of A/Indonesia/5/2005(H5N1) hemagglutinin (HA) to remove non–stem-reactive HA antibodies. Analysis of binding of preabsorbed sera to wild-type (WT) or (Δstem) A/Indonesia/5/2005(H5N1) HA was performed by ELISA. Detection of human antibodies was performed with an anti-human secondary antibody. Mean titers (±SD) are shown. P values between WT and Δstem binding for each group are 0.0071, 0.0001, 0.0019, 0.0406, 0.0129, and 0.0448, respectively. Statistical analyses were performed with a 2-tailed unpaired t test, using the Prism 5 program (GraphPad Software).