© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1381 Biotechnol. J. 2006, 1, 1381–1392 DOI 10.1002/biot.200600159 www.biotechnology-journal.com 1 Introduction The influenza virus belongs to the family Orthomyxoviri- dae comprising four genera: influenza A, B, and C viruses and thogotovirus (sometimes referred to as influenza D virus). Humans can be infected by influenza A, B, and C viruses, but only type A has caused pandemics; present- ing in turn a serious threat for humans. Two main surface glycoproteins of influenza virus, hemagglutinin (HA or H) and neuraminidase (NA or N) are responsible for the virus attachment and release from the host cell (Figs. 1 and 2). These proteins are also the main target for host antibod- ies. Type A viruses are subdivided into subtypes based on different combinations of 16 variants of HAs and 9 NAs. All known subtypes have been confirmed for wild birds, which are considered the natural host for influenza A viruses. Most of these viruses cause no significant illness in wild birds; however, they could induce severe disease and even death in domestic poultry such as chickens and turkeys. Only three subtypes, i.e., A(H1N1), A(H2N2), and A(H3N2), have been circulating so far in the human pop- ulation. These viruses together with influenza B strains are responsible for annual epidemics of various severities. Besides for birds and humans, type A viruses are infec- tious for pigs, horses, seals and whales. Influenza virus diversity is a genetically determined feature. Segmented negative-stranded RNA genome or- ganization of influenza virus facilitates the exchange of genomic segments (the so-called reassortment) between different strains during mixed infection. Furthermore, a lack of proofreading activity of influenza virus’ polymeriz- ing leads to high mutation rate of viral genes. Therefore, influenza strains with “new” antigenic properties regular- ly appear. If the change is sufficient to overcome the pre- existing immunity of the human population, the virus is capable of causing an epidemic. When the human popu- lation is completely naive of a newly appearing variant, the virus can readily infect and spread from infected to Review The fight against new types of influenza virus Julia Romanova Green Hills Biotechnology GmbH, Vienna, Austria In 1997, during an outbreak in chickens in Hong Kong the avian H5N1 influenza virus crossed the species barrier and infected 18 people, of which 6 cases were fatal. The virus also infected wild birds and continued to circulate and mutate in geese and ducks in southeastern China. Since this occurrence, new antigenic variants that are highly pathogenic for humans as well as wild, domes- tic, and exotic waterfowl continue to appear in Hong Kong. This virus is spreading across Asia, and is encroaching upon Europe and other continents. Wild birds are now considered as the main reservoir of H5N1 virus. Humans become infected with this H5N1 virus usually via close contact with infected birds or a highly contaminated environment. The very low transmissibility of this virus prevented further person-to-person dissemination in spite of the complete absence of im- munity in the human population to H5N1 viruses. Viruses of the H5N1 subtype are characterized by an exceptionally high pathogenicity for humans. The cause of the viral virulence is not known so far; however, several virulence factors are considered. The unprecedented capability of H5N1 viruses to kill humans intensifies the concern about its pandemic potential with catastrophic con- sequences. The effectiveness of existing antivirals as well as vaccines for humans and birds are re- viewed. Keywords: Virus · Influenza · Avian · Vaccine Correspondence: Dr. Julia Romanova, Green Hills Biotechnology GmbH, Gersthofer Str. 29–31, 1180, Vienna, Austria E-mail: j.romanova@greenhillsbiotech.com Fax: +43-1-319-6099 Abbreviations: HA or H, hemagglutinin; LAIV, live, attenuated, influenza vaccine; NA or N, neuraminidase; NS1, non-structural protein Received 17 August 2006 Revised 4 October 2006 Accepted 6 October 2006