Abstract
In spite of there being a number of vaccines, influenza remains a significant global cause of morbidity and mortality. Understanding more about natural and vaccine induced immune protection against influenza infection would help to develop better vaccines. Virus specific IgG is a known correlate of protection, but other factors may help to reduce viral load or disease severity, for example IgA. In the current study we measured influenza specific responses in a controlled human infection model using influenza A/California/2009 (H1N1) as the challenge agent. Volunteers were pre-selected with low haemagglutination inhibition (HAI) titres in order to ensure a higher proportion of infection; this allowed us to explore the role of other immune correlates. In spite of HAI being uniformly low, there were variable levels of H1N1 specific IgG and IgA prior to infection. There was also a range of disease severity in volunteers allowing us to compare whether differences in systemic and local H1N1 specific IgG and IgA prior to infection affected disease outcome. H1N1 specific IgG level before challenge did not correlate with protection, probably due to the pre-screening for individuals with low HAI. However, the length of time infectious virus was recovered from the nose was reduced in patients with higher pre-existing H1N1 influenza specific nasal IgA or serum IgA. Therefore, IgA contributes to protection against influenza and should be targeted in vaccines.
Highlights
Better understanding about how individuals are protected against influenza infection will aid vaccine development, by identifying effector mechanisms, and vaccine implementation, by identifying measurable correlates of protection (Reber and Katz, 2013)
Clinical challenge volunteers from two studies were used for this study, the first study was a dose escalation and the second study was a vaccine and challenge study; the high dose challenge group from study one was combined with placebo patients from study two
We were able to evaluate the role of IgA in the absence of serum inhibitory antibody because volunteers were pre-screened for low haemagglutination inhibition (HAI) titres
Summary
Better understanding about how individuals are protected against influenza infection will aid vaccine development, by identifying effector mechanisms, and vaccine implementation, by identifying measurable correlates of protection (Reber and Katz, 2013). Prospective population surveillance studies can be used as a tool to investigate the correlates of protection (Black et al, 2011), but they are large and expensive and because of the size of the studies, the number of potential correlates measurable may be restricted. An alternative is to use human infection challenge studies: whilst smaller in participant number they allow for an increased strike rate of infection, more intensive sampling and a known start point of infection (Carrat et al, 2008). The HAI titre that is currently used as a correlate of influenza protection was defined in the 1970s in a series of human influenza challenge studies (Hobson et al, 1972)
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