Evaluation of the Safety and Immunogenicity of a Candidate Pandemic Live Attenuated Influenza Vaccine (pLAIV) Against Influenza A(H7N9)

Abstract

Background: We evaluated a candidate A/Anhui/2013(H7N9) pandemic live attenuated influenza vaccine (pLAIV) in healthy adults, and assessed the ability of 1 or 2 doses to induce immune memory.

Methods: Healthy subjects in 2 age groups (18-49 years and 50-70 years) with undetectable hemagglutination-inhibiting (HAI) antibody to H7N9 were enrolled. Younger subjects received either 1 or 2 intranasal doses of 10(7.0) fluorescent focus units of A/Anhui/1/2013 pLAIV, while older subjects received a single dose. All subjects received a single 30-µg dose of unadjuvanted, antigenically matched A/Shanghai2/2013(H7N9) pandemic inactivated influenza vaccine (pIIV) 12 weeks after their first dose of pLAIV.

Results: Both vaccines were well tolerated. Serum HAI antibody responses were detected in 0 of 32 younger subjects and 1 of 17 older subjects after 1 dose of pLAIV and in 2 of 16 younger subjects after a second dose. Strong serum antibody responses were detected after a single subsequent dose of pIIV that was broadly reactive against H7 influenza viruses.

Conclusions: An A(H7N9) pLAIV candidate was safe in both age groups. Priming with pLAIV resulted in responses to subsequent pIIV that exceeded those seen in naive subjects in previous reports. The A(H7N9) pLAIV induces strong immune memory that can be demonstrated by exposure to subsequent antigenic challenge.

Clinical trials registration: NCT01995695 and NCT02274545.

Keywords: immune memory; live vaccine; pandemic influenza.

Figure 1.

Kinetics of the serum antibody response to a single dose of unadjuvanted A(H7N9) inactivated influenza vaccine (IIV) in younger subjects who previously received 1 dose (diamonds, dashed lines) or 2 doses (squares, solid lines), or older subjects (circles, dotted lines) who received 1 dose of A(H7N9) live attenuated influenza vaccine (LAIV). Data are for subjects considered responders by that specific test. A, Results of the hemagglutination-inhibition assay, using the A(H7N9) LAIV and horse red blood cells. B, Results of the microneutralization assay, using the A(H7N9) LAIV. C, Results of the immunoglobulin G–specific enzyme-linked immunosorbent assay (ELISA), using baculovirus-expressed A/Anhui/1/13(H7N9) hemagglutinin. D, Results of the immunoglobulin A–specific ELISA, using baculovirus-expressed A/Anhui/1/13(H7N9) hemagglutinin. ELISA was only performed on sera obtained from younger subjects. Abbreviation: GMT, geometric mean titer.

Figure 2.

Neutralizing antibody titers against wild-type influenza A(H7N9) viruses. Sera collected 28 days after inactivated influenza vaccine boost in younger recipients of 1 (left) or 2 (right) doses of live attenuated influenza vaccine priming were tested by microneutralization (MN) assay against the following wild-type H7 influenza viruses under biosafety level 3 conditions: A/Anhui/1/2013 (H7N9, human; A), A/Hong Kong/734/2014 (H7N9, human; B), A/Netherlands/219/2003 (H7N7, human; C), A/ck/British Columbia/CN-7/2004 (H7N3, avian; D). Data are shown for sera that had a titer of ≥1:32 against the homologous influenza A/Anhui/1/2013 virus. The solid bar represents the mean.

Figure 3.

Induction of A(H7N9)-specific antibody-dependent cellular cytotoxicity (ADCC) following a pandemic live attenuated influenza vaccine (pLAIV) and pandemic inactivated influenza vaccine (pIIV) regimen. ADCC titer to rH7 hemagglutinin (A/Anhui/01/2013) in serum obtained from younger subjects at day 0 and day 28 following receipt of either 1 dose (n = 14) or 2 doses (n = 16) of A(H7N9) pLAIV (A and B) and following receipt of an A(H7N9) pIIV boost (C and D). The line indicates the geometric mean value for the group. *P < .05, by the Student t test.