Demonstration by European team of a human monoclonal antibody capable of neutralizing all types of influenza A virusesArchived

Corti D, Voss J, Gamblin SF, et al. A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins. Science Express 2011 Jul 28

The team used a novel culture, scan and screening technique to quickly investigate multiple early plasma cells and their antibodies from a small number of human volunteer donors. They were selected on the basis of them being known to produce strong antibody responses of a range of antibodies from previous natural infections and immunisation.  As a results the team harvested a range of human monoclonal antibodies which were tested against heterologous haemagglutinins from the two major HA groups Group 1 and Group 2 (see ECDC Comment below to explain meaning). Over 100,000 plasma cells were investigated from eight donors. One donor who was naturally infected with the A(H1N1)2009 in 2009 and then immunised with seasonal influenza vaccine (containing A(H1), A(H3) and B antigens) in early 2010 produced some antibodies that cross-reacted with both Group 1 and Group 2 influenza viruses.  A particular antibody designated F16 with this capacity was identified from four plasma cells. Genetic material from these was used to clone into expression vectors and hence recombinant F16 antibody was produced in some volume by infecting an established cell line with the vectors. After modification these monoclonal antibodies were tested for their protective effects in animal models challenged with natural influenza viruses from both Groups 1 and Group 2 viruses. The antibodies were found to protect against challenges that normally would be lethal to the animals and to have both treatment and protective effects.  The F16 antibody was rare in the human donors. The other donors produced some antibodies that could just bind to haemagglutinins from both Group 1 and 2 but it was only F16 that could neutralize the infectivity of the viruses. The antibody was also rare in the source donor. It was not found among around 20,000 B memory cell clones from that donor.  The researchers also investigated the structural basis of the effect they had described by use of complex crystallography and genetic manipulation discovering that it was binding to what is called the F-subdomain of haemagglutinins. Though they could not determine exactly how neutralization worked they suggest a number of possible mechanisms including inhibition of syncytial formation, blocking of extracellular viral cleavage, and interference in viral assembly.(1) 

ECDC Comment (30 July 2011): Important human antibodies that act against and neutralize the infectivity of influenza viruses are those that work against the haemagglutinin proteins (HAs) of the viruses. Hemagglutinin (HA) is the major envelope glycoprotein of influenza A viruses and the target of almost all neutralizing antibodies. HA is produced as an immature polypeptide chain called HA0, which is cleaved and so activated by human or other animal host proteases to yield two subunits. Sixteen distinct sub-types of HAs have been reported (not all infect humans readily) and they cluster into two distinct groups classified on the basis of their primary genetic sequence.(2) Group 1 HAs comprise ten of the sixteen H subtypes: H1, H2, H5, H6, H8, H9, H11, H12, H13, and H16. While Group 2 HAs account for the remaining six: H3, H4, H7, H10, H14 and H15).  Other studies have found sets of antibodies that can bind to and neutralize multiple influenza A viruses in Group 1 or Group 2, but not to both.(3,4) This is therefore an important scientific advance in a highly competitive field, especially given the demonstration of protective and treatment  effectiveness in animals models usually considered relevant to humans (mice and ferrets).(1)

This finding has two possible clinical implications, for treatment and prevention (vaccination). Firstly there is the possibility of producing monoclonal antibodies for treatment of influenza cases. This is not a new idea. The proposal of using convalescent sera from people who have recovered from a novel influenza to treat those with severe disease goes back at least to the pandemic of 1918 and some pooled immunoglobulins were used in intensive care units in the 2009 pandemic.(5) However it would need a trial and here difficulties arise. Since most influenza infections are mild a trial on severe influenza cases, would be required in settings like intensive care units.(5) This is conceivable but has to take into account that influenza operates to cause severe disease through a number of mechanism including secondary (bacterial) infections and cardio-vascular events.  So that by the time that an antibody was given it may be that the disease process it is targeting has already had its effect. Also a commercial company would presumably need to be persuaded to develop the monoclonal antibody and support a trial for what would be a limited market. What is more promising is if this advance could be used to develop broadly protective or universal flu vaccine by to isolating the haemagglutinin stem region targeted by this  antibody and then using that in influenza vaccines to eventually develop a universal influenza A vaccine.