Reply to Lindsey, Höschler, and de Silva

To the Editor—We are thankful for the comments made by Lindsey et al [1], which enrich the current discussions on identifying immune mechanisms in response to vaccination with the live-attenuated influenza vaccine (LAIV) and on finding possible explanations for the discrepancies observed in LAIV vaccine effectiveness studies in different countries and settings.

In our article [2], we focused on serum antibodies for three main reasons. First, hemagglutinin inhibition (HAI) pre-immunization titers have been shown, for example [3, 4] to strongly correlate with LAIV shedding and immunogenicity. Indeed, in their original publication [5] the authors found a strong inverse relationship between baseline HAI titers and viral shedding for 3 out of 4 of the vaccine strains considered in that study (H3N2, B and H1N1 [NY15] strains of the LAIV vaccine), in agreement with the hypothesis that preexisting immunity would indeed preclude viral shedding from a closely related vaccine strain. Further, the data presented by Lindsey et al [1] is consistent with the hypothesis: figure 1A, B and C (first panel) shows that children who were seropositive to the strain contained in the vaccine were less likely to shed virus and seroconvert. Second, measurement of HAI titers is the marker that has been historically used by the Advisory Committee on Immunization Practices to develop recommendations for the use of LAIV [6, 7]. Finally, we aimed to construct the most parsimonious model that would allow us to explain the differences observed in vaccine effectiveness in different studies.

We agree with Lindsey et al that cellular and mucosal responses are important components of the immune response, but the extent of the contribution of each of them has not been well identified [8]. Interestingly, in the data presented by Lindsey et al (Figure 1C, last panel) [1], only a small percentage of children (<25%) in all the groups considered elicited an immunoglobulin A (IgA) response, making us question the importance of the mucosal response as a predictor of LAIV immunogenicity in this particular study. We believe that more thorough analyses are needed to understand the role of the mucosal IgA response.

We agree with Lindsey et al that the immune response to the LAIV is complex and poorly understood, and that more studies need to be done. In particular, we believe that it is crucial to invest in immunogenicity studies that will correctly identify correlates of protection for LAIV. Once these are known, mathematical models, like ours, can be refined to include more complex immune interactions.

Notes

Financial support. This work was supported by the National Institute of General Medical Sciences (grant number: U54GM111274) and the National Institute of Allergy and Infectious Diseases (grant number: U19 AI117891) of the National Insitutes of Health.

Potential conflicts of interest. All authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.