Abstract
BackgroundHigh hemagglutination inhibition (HAI) and neuraminidase inhibition (NAI) titers are generally associated with reduced influenza risk. While repeated influenza vaccination reduces seroresponse, vaccine effectiveness is not always reduced.MethodsDuring the 2007-2008 influenza season, a randomized, placebo-controlled trial (FLUVACS) evaluated the efficacies of live-attenuated (LAIV) and inactivated influenza vaccines (IIV) among healthy adults aged 18-49 in Michigan; IIV vaccine efficacy (VE) and LAIV VE against influenza disease were estimated at 68% and 36%. Using the principal stratification/VE moderation framework, we analyzed data from this trial to assess how each VE varied by HAI or NAI responses to vaccination observed for vaccinated individuals and predicted counterfactually for placebo recipients. We also assessed how each VE varied with pre-vaccination/baseline variables including HAI titer, NAI titer, and vaccination history.ResultsIIV VE appeared to increase with Day 30 post-vaccination HAI titer, albeit not significantly (p=0.20 and estimated VE 14.4%, 70.5%, and 85.5% at titer below the assay lower quantification limit, 512, and 4096 (maximum)). Moreover, IIV VE increased significantly with Day 30 post-vaccination NAI titer (p=0.040), with estimated VE zero at titer 10 and 92.2% at highest titer 640. There was no evidence that fold-change in post-vaccination HAI or NAI titer associated with IIV VE (p=0.76, 0.38). For LAIV, there was no evidence that VE associated with post-vaccination or fold-rise HAI or NAI titers (p-values >0.40). For IIV, VE increased with increasing baseline NAI titer in those previously vaccinated, but VE decreased with increasing baseline NAI titer in those previously unvaccinated. In contrast, for LAIV, VE did not depend on previous vaccination or baseline HAI or NAI titer.Conclusions: Future efficacy trials should measure baseline and post-vaccination antibody titers in both vaccine and control/placebo recipients, enabling analyses to better elucidate correlates of vaccine- and natural-protection.Trial registration: ClinicalTrials.gov NCT00538512. October 1, 2007.
Highlights
High hemagglutination inhibition (HAI) and neuraminidase inhibition (NAI) titers are generally associated with reduced influenza risk
There was a significant interaction between inactivated influenza vaccine (IIV), Evervax, and Day 0 NAI (p=0.006); this interaction means that vaccine efficacy (VE) as a function of Day 0 NAI titer differs for the Evervax Yes and No subgroups
Higher pre-vaccination/baseline HAI titers were observed among the previously vaccinated than among the previously unvaccinated, while no difference in NAI titers was observed. These findings suggest that NAI titers decay faster than HAI titers after vaccination or are not boosted as much by vaccination as HAI titers. The former explanation is unlikely considering that post-vaccination HAI and NAI titers have been observed to wane at similar rates [21, 51], while the latter explanation is supported by the fact that the NA concentration is not standardized in currently licensed influenza vaccines
Summary
High hemagglutination inhibition (HAI) and neuraminidase inhibition (NAI) titers are generally associated with reduced influenza risk. Serum levels of anti-HA antibodies are measured by the hemagglutination inhibition (HAI) assay. When assay targets are well matched to circulating viruses, there is generally a clear relationship between increasing HAI titer and decreasing infection risk [3,4,5,6,7,8,9]; some individuals acquire infection or experience influenza disease despite high HAI titers [4, 10,11,12] or seroconversion [12]. As measured by neuraminidase inhibition (NAI) assays, anti-NA antibodies play an independent role in protection from influenza disease and/or in reducing influenza disease severity [14, 15]
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