A Randomized Controlled Trial to Compare Immunogenicity to Cell-Based Versus Live-Attenuated Influenza Vaccines in Children

Abstract

Background: Few studies have focused on the immune response to more recent influenza vaccine formulations such as cell-cultured inactivated influenza vaccine (ccIIV4) or live-attenuated influenza vaccine (LAIV4) in older children and young adults, or differences in immunoglobulin response using newer antibody landscape technology.

Methods: Participants ages 4-21 were randomized to receive ccIIV4 (n = 112) or LAIV4 (n = 118). A novel high-throughput multiplex influenza antibody detection assay was used to provide detailed IgG, IgA, and IgM antibody isotypes, along with hemagglutination inhibition levels (HAI), measured pre- and 28 days post-vaccination.

Results: The HAI and immunoglobulin isotype response to ccIIV4 was greater than LAIV4, with significant increases in IgG but not IgA or IgM. The youngest participants had the highest LAIV4 response. Prior LAIV4 vaccination was associated with a higher response to current season ccIIV4. Cross-reactive A/Delaware/55/2019(H1N1)pdm09 antibodies were present pre-vaccination and increased in response to ccIIV4, but not LAIV4. Immunoglobulin assays strongly correlated with and confirmed the findings of HAI titers to measure immune response.

Conclusions: Age and prior season vaccination may play a role in the immune response in children and young adults to ccIIV4 and LAIV4. While immunoglobulin isotypes provide high-level antigen-specific information, HAI titers alone can provide a meaningful representation of day 28 post-vaccination response.

Clinical trials no: NCT03982069.

Keywords: MIADA; cell-culture-based inactivated influenza vaccine; egg-based live-attenuated influenza vaccine; hemagglutination inhibition assay; influenza; influenza vaccine; randomized controlled trial.

Figure 1.

Consort flow diagram.

Figure 2.

Antibody responses by multiplex influenza antibody detection assay (MIADA) following cell-based quadrivalent inactivated influenza vaccine (ccIIV4) and egg-based quadrivalent live-attenuated influenza vaccine (LAIV4). The paired pre- (day 0) and post-vaccination (day 28) serum samples collected from either ccIIV4 or LAIV4 vaccine recipients were analyzed for IgG, IgA, or IgM responses in MIADA. All paired samples were analyzed for IgG, IgA, or IgM responses in MIADA assay. Mean MFI and 95% confidence intervals are shown.

Figure 3.

Mean fold rise in hemagglutination inhibition (HAI) and immunoglobulin G isotype (IgG) median fluorescence intensity (MFI) antibody responses among 3 age groups following cell-based quadrivalent inactivated influenza vaccine (ccIIV4) and egg-based quadrivalent live-attenuated influenza vaccine (LAIV4). All serum specimens were tested by HAI antigens (4a and 4b) include five 2020-21 vaccine reference viruses (A/Hawaii/66/2019(H1N1)pdm09 [egg-propagated A/Guangdong-Maonan/SWL1536/2019-like egg-based vaccine reference virus], A/Hawaii/70/2019(H1N1)pdm09 [cell-propagated A/Hawaii/70/2019-like cell-based vaccine reference virus], A/Hong Kong/2671/2019(H3N2) [egg], B/Washington/02/2019 (B/Victoria) [egg], and B/Phuket/3073/2013 (B/Yamagata) [egg]). IgG MFI responses HA1 globular head (G) or HA stalk antigens from recent A(H1N1)pdm09, A(H3N2) and influenza B viruses and nucleoprotein (NP) from A(H3N2), (4c and 4d). Mean fold rise and 95% confidence interval in HAI titers and MFI values are shown. *Mann Whitney test for comparison with 4-11-year-olds, P < 0.05.

Figure 4.

Mean fold rise in hemagglutination inhibition (HAI) and immunoglobulin G isotype (IgG) median fluorescence intensity (MFI) antibody for 2020 cell-based quadrivalent inactivated influenza vaccine (ccIIV4) recipients who received either ccIIV4 or egg-based quadrivalent live-attenuated influenza vaccine (LAIV4) in 2019. The 2020 ccIIV4 vaccine recipients were grouped by prior year vaccine type, ccIIV4 (n = 21) and LAIV4 (n = 23). Closed circles represent 2019 ccIIV4 and open diamonds 2019 LAIV4. All paired samples were tested by HAI (a) antigens including five 2020-21 vaccine reference viruses (A/Hawaii/66/2019(H1N1)pdm09 [egg-propagated A/Guangdong-Maonan/SWL1536/2019-like egg-based vaccine reference virus], A/Hawaii/70/2019(H1N1)pdm09 [cell-propagated A/Hawaii/70/2019-like cell-based vaccine reference virus], A/Hong Kong/2671/2019(H3N2) [egg], B/Washington/02/2019 (B/Victoria) [egg], and B/Phuket/3073/2013 (B/Yamagata) [egg]) and MIADA IgG MFI responses (b) to HA1 globular head (G) or HA stalk antigens from recent A(H1N1)pdm09, A(H3N2) and influenza B viruses. Mean fold rise and 95% confidence interval in HAI titers and MFI values are shown. *P < 0.05 for comparison to 2019 ccIIV4 group.