Assessment of immune responses to H5N1 inactivated influenza vaccine among individuals previously primed with H5N2 live attenuated influenza vaccine

Abstract

During the past decade, a number of H5 subtype influenza vaccines have been developed and tested in clinical trials, but most of them induced poor serum antibody responses prompting the evaluation of novel vaccination approaches. One of the most promising ones is a "prime-boost" strategy, which could result in the induction of prompt and robust immune responses to a booster influenza vaccine following priming with homologous or heterologous vaccine strains. In our study we evaluated immunogenicity of an adjuvanted A(H5N1) inactivated influenza vaccine (IIV) in healthy adult subjects who received A(H5N2) live attenuated influenza vaccine (LAIV) 1.5 years earlier and compared this with a group of naïve subjects. We found that priming with A(H5N2) LAIV induced a long-lasting B-cell immunological memory against influenza A(H5N1) virus, which was brought on by more prompt and vigorous antibody production to a single dose of A(H5N1) IIV in the primed group, compared to the naïve controls. Thus, by day 28 after the first booster dose, the hemagglutination inhibition and neutralizing (MN) antibody titer rises were 17.2 and 30.8 in the primed group, compared to 2.3 and 8.0 in the control group, respectively. The majority (79%) of the primed individuals achieved seroprotective MN antibody titers at 7 days after the first dose of the IIV. All LAIV-primed volunteers had MN titers ≥ 1:40 by Day 28 after one dose of IIV, whereas only 58% subjects from the naïve control group developed similar immune responses at this time point. The second A(H5N1) IIV dose did not increase the immune response in the LAIV-primed group, whereas 2 doses of IIV were required for naïve volunteers to develop significant immune responses. These findings were of special significance since Russian-based LAIV technology has been licensed to WHO, through whom the vaccine has been provided to vaccine manufacturers in India, China and Thailand - countries particularly vulnerable to a pandemic influenza. The results of our study will be useful to inform the development of vaccination strategies in these countries in the event of a pandemic.

Keywords: H5 avian influenza viruses; clinical trial; inactivated influenza vaccine; live attenuated influenza vaccine; memory immune response; prime-boost strategy; safety.

Figure 1.

Study flow chart.

Figure 2.

Serum antibody titers to A/17/turkey/Turkey/05/133 (H5N2) in volunteers before vaccination with A(H5N1) IIV (Day 0). Dots– individual data of volunteers vaccinated with H5N2 LAIV in 2012 (n=19), and non-vaccinated with LAIV in 2012 (n = 24); lines– Ab GMTs.P values were calculated using GraphPad Prism 5 software by Mann Whitney U test.

Figure 3.

Antibody titers in supernatants of PBMC cultures (ALS) in LAIV-primed (n = 19) and control (n = 24) volunteers at indicated study days after boost immunization with A(H5N1) IIV. (A) NIBRG-23 (H5N1) virus was used as antigen. (B) A/17/turkey/Turkey/05/133 (H5N2) virus was used as antigen. lines– geometric mean titers of antibodies. P values were calculated from log₂-transformed titers using GraphPad Prism 5 software by Mann Whitney U test.