Pre-existing immunity in human challenge studies of influenza transmission

Abstract

I was encouraged to read the Personal View by Ben Killingley and colleagues regarding the use of human challenge studies for the investigation of infl uenza transmission. Despite the often cited studies with guineapigs and ferrets, these volunteer challenge studies have far greater relevance to the transmission of infl uenza between people. Killingley and colleagues summarise the benefi ts and prob lems of undertaking and inter preting the results of such studies com prehensively, but do not go into great detail about the potential confounding eff ects of pre-existing, hetero logous (cross-reacting) im munity in their volunteers, which could aff ect several variables of interest, such as host viral shedding (load and duration), typical viral loads produced in exhaled aerosols, and the infectious doses that cause symptomatic disease. With each infl uenza pandemic, the previous infl uenza A subtype is eventually replaced by the subsequent pandemic subtypes. Early work by Schild and colleagues recognised this occurrence and suggested that “immunological ‘memory’ may exist between the surface antigens of viruses of diff erent subtypes”. Although at that time they stated that the immunological role of one of the other viral antigens, the membrane protein, was unknown, this particular antigen has become one of the targets for the development of a universal infl uenza vaccine, because it is more conserved than either of the other surface proteins—haemagglutinin or neuraminidase. The presence of such conserved antigens that produce a more universal immunity across diff erent infl uenza A subtypes could aff ect the immunological make-up of human volunteers enrolled into these challenge studies and introduce a potential confounder that might be diffi cult to control. Yet, such antigens are known to be undetectable with standard serological assays. One practical way to overcome such problems is to develop immunological assays able to more fully characterise the immunological profi le of each volunteer enrolled, with respect to each of the viral antigens present in the infl uenza A subtypes under investigation. Without such profi ling, the results of human challenge studies might still be open to interpretation. I would be interested to know how Killingley and colleagues’ group plan to deal with this problem, should they take such human challenge studies forward. A well planned and executed study will be invaluable in the present climate where vast resources are now allocated to preventing, controlling, and treating infl uenza infection and its related complications.