Highlights
- •Repeated inactivated influenza vaccination boosts bNAbs
- •Inactivated and live attenuated vaccines are similarly efficient at boosting bNAbs
- •The magnitude of IIV and LAIV vaccine-elicited bNAb boosting declines with age
Summary
The induction of broadly neutralizing antibodies (bNAbs) that target the hemagglutinin stalk domain is a promising strategy for the development of “universal” influenza virus vaccines. bNAbs can be boosted in adults by sequential exposure to heterosubtypic viruses through natural infection or vaccination. However, little is known about if or how bNAbs are induced by vaccination in more immunologically naive children. Here, we describe the impact of repeated seasonal influenza vaccination and vaccine type on induction of bNAbs against group 1 influenza viruses in a pediatric cohort enrolled in randomized controlled trials of seasonal influenza vaccination. Repeated seasonal vaccination results in significant boosting of a durable bNAb response. Boosting of serological bNAb titers is comparable within inactivated and live attenuated (LAIV) vaccinees and declines with age. These data provide insights into vaccine-elicited bNAb induction in children, which have important implications for the design of universal influenza vaccine modalities in this critical population.
Introduction
Despite decades of study and the accessibility of seasonal vaccination, influenza remains an important public health concern, largely owing to its ability to escape immunity and cause seasonal epidemics and pandemics.1, 2, 3 Seasonal vaccines, the mainstay of influenza prevention, have often shown modest real-world effectiveness due to suboptimal immunogenicity, alongside rapid and unpredictable changes in circulating virus strains.1, 2, 3 Globally, several different seasonal influenza vaccine formulations are approved, including intramuscular injection of inactivated virus (IIV) or mucosal administration of replication-competent live attenuated influenza vaccine (LAIV).1 Although influenza vaccines are often considered equally efficacious, there are insufficient data on the impact of repeated vaccination and vaccine type on the breadth of influenza-virus-directed immunity in specific demographic groups, especially children, who are a major source of influenza transmission and, alongside the elderly, are at heightened risk for influenza-related hospitalizations and death.4,5The bulk of influenza-vaccine-elicited antibodies (Abs) target the viral membrane surface proteins hemagglutinin (HA) and, to a lesser extent, neuraminidase (NA). Of the HA-reactive Abs, most bind the “immunodominant” globular HA head domain in a strain-specific manner, blocking the interaction between the virus and cell surface sialic acid, while a minority of HA-reactive Abs bind the sub-dominant, but highly conserved HA stalk domain; a subset of these Abs is considered broadly neutralizing (bNAbs). HA stalk-reactive bNAbs have emerged as a promising strategy for the development of a “universal” influenza vaccine.6,7In adults, we and others have shown that bNAbs are selectively boosted by exposure to pandemic/heterosubtypic HA subtypes (via either infection or vaccination).8, 9, 10 bNAb titers also increase over time owing to an accumulation of lifetime exposures to influenza virus selecting for cross-reactive B cell clone maintenance and expansion.11,12 A recent clinical trial demonstrated that chimeric hemagglutinin vaccines delivered in live attenuated and inactivated formulations could successfully boost bNAb titers in adults.6,7 However, little is known about how bNAbs develop in children and how vaccination impacts bNAb development—knowledge that will have important implications for understanding the nature of vaccine-mediated immunity against influenza, especially in the context of exposure to novel strains.1,13,14Therefore, we explored the effects of seasonal influenza vaccination and vaccine formulation on bNAb induction in participants of a cluster randomized controlled trial (cRCT) designed to compare the community-level protection mediated by IIV and LAIV vaccination of children. We found that titers of neutralizing bNAbs were enhanced by repeated seasonal vaccination and that bNAb levels were boosted similarly by LAIV and IIV. As expected, LAIV and IIV effects on bNAb titers were more pronounced in the mucosa and blood, respectively, and the magnitude of vaccine-induced bNAb responses in the serum declined with age.
Results
Study participants
The effects of repeated seasonal IIV vaccination on the induction of bNAbs were studied using serum samples from 68 RCT participants (median age 9.0 years) (Table S1), who either received IIV (37 vaccinees) or served as controls (31 controls) for each of the three seasons (2008/09 to 2010/11) captured by the cRCT (Figure 1A and Table 1) and for whom paired samples were available. The effects of vaccine type on bNAb elicitation were subsequently studied using serum and mucosal samples from 72 RCT participants (median age 11.0 years) (Table S1), who received either the inactivated vaccine (IIV, n = 35) or the live attenuated vaccine (LAIV, n = 37) (Figure 1B and Table 1) and for whom paired samples were available…
