Advancing treatment options for influenza: challenges with the human influenza challenge.

Current therapeutic options for the treatment of influenza virus infections are limited. Only 2 classes of agents have licensed products, neuraminidase (NA) inhibitors and M2 inhibitors, and only NA inhibitors are active against currently circulating seasonal viruses. While observational studies show a benefit of NA inhibitor treatment for hospitalized patients with influenza [1], optimal treatment for severely ill patients and those who are immunocompromised will likely require additional treatment options with a different mechanism of action. Since the 1918 pandemic, convalescent serum or plasma from persons previously infected with influenza virus has been investigated as treatment for individuals with severe influenza virus infection, including, more recently, individuals with human avian influenza and 2009 pandemic A(H1N1) infections [2, 3]. However, receipt of convalescent serum can be associated with severe adverse effects, and the resources necessary to produce such serum in large quantities are prohibitive [2]. Compared with convalescent serum, human monoclonal antibodies (mAbs) against influenza viruses may be more feasible for widespread use, without the adverse effects associated with human blood products. However, identifying a human mAb that can reproduce the clinical anti–influenza virus effects of polyclonal convalescent serum is a challenge. A handful of mAbs against influenza virus proteins are currently in early phases of evaluation for human use [4]. In this issue of The Journal of Infectious Diseases, Ramos et al report results from a human influenza challenge study evaluating the effect on clinical illness of a human mAb targeting the external portion (ie, ectodomain) of the M2 protein (M2e) [5]. M2 protein is an attractive target for broadly cross-reactive influenza vaccines and therapeutic Abs because of the highly conserved nature of the amino acid sequences of its ectodomain among isolates from different antigenic subtypes of influenza A viruses [6]. A number of mAbs targeting either linear or conformational epitopes within M2e have been described [7–11]. Studies in mouse models have shown that passive transfer of anti-M2 mAbs into recipient mice can offer survival advantages against lethal viral challenges and reduce virus replication in the lungs; however, the degree of the therapeutic effect varied depending on the particular mAb, challenge virus, and other factors [8, 12–14]. The mechanisms of anti-M2e Ab– mediated protection are not fully understood. Anti-M2 Abs do not possess hemagglutination inhibition ability or in vitro virus neutralization activity [15]. It is believed that the main target for the anti-M2e antibody is virus-infected cells, which abundantly express M2 protein on their surface [16]. Conceivably, by binding to M2e, the nonneutralizing anti-M2 Abs may facilitate elimination of virus-infected cells in vivo by triggering complement-dependent cytotoxicity and/or antibody-dependent cell-mediated cytotoxicity [12, 15]. The involvement of alveolar macrophages in humoral M2especific protection by phagocytosis has been reported [17]. Moreover, the possibility of an alternative mechanism of protection (eg, interference with M2 ion channel activity) was suggested for an anti-M2e mAb that targeted dimeric or multimeric M2 peptides [10]. Elimination of infected cells results in reduction of virus replication and spread. However, concerns have been raised with regard to a potential disease exacerbating effect of nonneutralizingAbs, presumably through the similar immune mechanisms, as observed in the swine model of influenza [18, 19]. Evaluation of any new anti–influenza therapeutics, such as anti-M2e mAb, in humans is a daunting task. Human challenge models were developed to aid in such evaluations. Challenging healthy adult volunteers with a well-characterized influenza virus provides several advantages: synchronization of infection and illness course, prescreening for susceptible participants by testing for Abs against the hemagglutinin of the challenge virus, and knowledge of baseline symptoms and Received 23 September 2014; accepted 23 September 2014; electronically published 3 October 2014. Correspondence: Alicia M. Fry, MD, MPH, 1600 Clifton Rd, MS A-32, Atlanta, GA 20329 ([email protected]). The Journal of Infectious Diseases 2015;211:1033–5 Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. Thiswork iswritten by (a) US Government employee(s) and is in the public domain in the US. DOI: 10.1093/infdis/jiu543