Fast rise of broadly cross-reactive antibodies after boosting long-lived human memory B cells primed by an MF59 adjuvanted prepandemic vaccine

Abstract

Proactive priming before the next pandemic could induce immune memory responses to novel influenza antigens. In an open-label study, we analyzed B cell memory and antibody responses of 54 adults who received 2 7.5-microg doses of MF59-adjuvanted A/Vietnam/1194/2004 clade 1 (H5N1) vaccine. Twenty-four subjects had been previously primed with MF59-adjuvanted or plain clade 0-like A/duck/Singapore/1997 (H5N3) vaccine during 1999-2001. The prevaccination frequency of circulating memory B cells reactive to A/Vietnam/1194/2004 was low in both primed and unprimed individuals. However, at day 21 after boosting, MF59-adjuvanted primed subjects displayed a higher frequency of H5N1-specific memory B cells than plain-primed or unprimed subjects. The immune memory was rapidly mobilized by a single vaccine administration and resulted in high titers of neutralizing antibodies to antigenically diverse clade 0, 1, and 2 H5N1 viruses already at day 7. In general, postvaccination antibody titers were significantly higher in primed subjects than in unprimed subjects. Subjects primed with MF59-adjuvanted vaccine responded significantly better than those primed with plain vaccine, most notably in early induction and duration of cross-reacting antibody responses. After 6 months, high titers of cross-reactive antibody remained detectable among MF59-primed subjects. We conclude that distant priming with clade 0-like H5N3 induces a pool of cross-reactive memory B cells that can be boosted rapidly years afterward by a mismatched MF59-adjuvanted vaccine to generate high titers of cross-reactive neutralizing antibodies rapidly. These results suggest that pre-pandemic vaccination strategies should be considered.

Conflict of interest statement

Conflict of interest statement: The sponsor is an employee of Novartis Vaccines, Siena, Italy. A.B., M.B., V.B., F.C., G.D.G., G.G., C.M., and M.P. are employees of Novartis Vaccines and Diagnostics. K. Hoschler, E.M., K.N., and I.S. have received support from vaccine producers including Novartis Vaccines for scientific research, speaker's fees, and attendance at scientific meetings. The Health Protection Agency has received funding for vaccine immunogenicity trials from manufacturers including Novartis Vaccines.

Figures

Fig. 1.

The frequency of H5N1-IgG memory B cells (H5N1-IgG MBC) before and after vaccination in individual subjects from unprimed (open triangles), plain-primed (open circles), and MF59 primed groups (open diamonds). Mean values area indicated by horizontal lines. P-values for significant differences were obtained by 1-factor ANOVA. Syringe indicates vaccine administration.

Fig. 2.

Antibody responses following administration of MF59-adjuvanted NIBRG-14 vaccine. Geometric mean titers (GMT) of antibody and geometric mean areas (GMA) from unprimed (open triangles), plain-primed (open circles), and MF59-primed groups (open diamonds) by hemagglutinin-inhibition (HI) (Upper), neutralization (MN) (Middle), and single radial (SRH) hemolysis (Lower) are shown. Dotted lines indicate titers of HI 1:32; MN 1:40; and SRH 25 mm2. Syringe indicates vaccine administration.

Fig. 3.

Neutralizing responses to wild-type H5N1 and priming clade 0 H5N3 viruses following MF59-adjuvanted NIBRG-14 vaccine. Mean geometric mean titers (MN GMT) of antibody from unprimed (Left), plain-primed (Middle), and MF59-primed (Right) groups. Virus strains are clade 0: A/duck/Singapore/97 (filled sqaures), A/Hong Kong/156/97 (open circles); clade 1: A/Vietnam/1194/2004 (open circles), A/Cambodia/R0405050/2007(filled circles); clade 2.3.4: A/Anhui/1/2005(gray triangle); clade 2.1.3 A/Indonesia/5/2005 (open triangles); and clade 2.2: A/Turkey/15/2006 (black triangle). Dotted line shows titer of 1:40. Syringe indicates vaccine administration.