Influenza Adrift: Rethinking Hemagglutinin Antigenic Evolution

s S5 modulate antigenicity and receptor binding, confounds retrospective analysis of genetic variation in HA. The situation is complicated further by the occurrence of epistatic changes within HA and between HA and NA to maximizeviral fitness following selection. Moreover, substitutions selected to modulate receptor avidity will inevitably modify receptor specificity for various sialic acid terminated-glycans and vice versa. From leaves to forest: even in the simplest species (viruses), evolution is complicated, and oversimplified analysis leads to all sorts of errors, including those with practical ramifications in interpreting sequences for choosing vaccine strains. doi:10.1016/j.phrp.2011.11.021 Lessons Learnt from (HIN1)2009 Influenza Pandemic for Preparedness Against Future Pandemics Masato Tashiro Director, WHO Collaborating Centre for Research and Reference on Influenza Influenza Virus Research Center, National Institute of Infectious Diseases, Japan. Pandemic (H1N1) 2009 was relatively mild with less severe disease burdens and social impact. Pandemic (H1N1)pdm09 virus itself was low pathogenic, similar to seasonal flu viruses and different from H5N1 highly pathogenic avian influenza viruses. Most people had acquired immunity to Spanish flu or former seasonal H1N1 flu viruses, which was cross-protective, in part, against H1N1pdm09 virus. The pandemic started in the North America, where US CDC detected and identified the causative virus rapidly, sharing information with WHO to take immediate responses. Most countries had been prepared, more or less, against a possible pandemic by H5N1. H1N1pdm09 virus hardly underwent antigenic drift and the pandemic vaccine remained matched and effective. The virus was susceptible to neuraminidase inhibitors and drug-resistant viruses did not spread, unlike former seasonal H1N1 virus during 2007-2009. The pandemic virus did not increase the pathogenicity, unlike Spanish flu in 1918/19. Finally, disease burdens and social impact remained far below previous assumptions against a possible H5N1 pandemic. On the other hand, pandemic vaccine production and supply were delayed and insufficient and much confusion occurred due to misleading by health authorities and media. It appeared clear that implementation of pandemic preparedness plans had been suboptimal in many settings. During the pandemic (H1N1)2009, H5N1 highly pathogenic avian influenza continued to spread in several areas causing human infections. WHO is keeping its pandemic alert level Phase 3. Both H1N1pdm09 and H5N1 viruses were shown to infect pigs in China and Indonesia and therefore, gene reassortment between the viruses may occur in pigs or humans. Risk of an H5 pandemic still remains or is increasing, which will cause extremely heavy disease burdens and social disruptions. We should also learn much from the devastating earthquakes and tsunami and the resultant nuclear power plant accident, which occurred at much severer levels far beyond the government’s “optimistic assumptions”, bases for the suboptimal preparedness. The worst thing we can do is not prepare for a worst case scenario and think it will not happen. We must be prepared against a worst-case scenario of pandemic influenza caused by a highly pathogenic virus. doi:10.1016/j.phrp.2011.11.022 Strategies for Control of Pandemic Influenza: Active and Passive Immunization Huan H. Nguyen Head of the Viral Immunology Section, International Vaccine Institute, Seoul, Korea. Pandemic influenza poses a serious threat to global health and the world economy. Highly pathogenic avian influenza A virus (HPAIV) of the H5N1 subtype that has emerged since 2004, resulted in more than 430 cases in 15 countries with a 50% case-fatality rate. Novel vaccine strategies for early response include the use of attenuated vaccines/vectors administered via novel mucosal immunization routes, therapeutic anti-virals and passive immunization with virus-specific antibodies (Abs). The current influenza vaccines designed for inducing antibody (Ab) responses against viral surface antigens (i.e., hemagglutinin [HA] and neuraminidase [NA]) are limited to seasonal use because of the ability of the virus to mutate these major antigenic glycoproteins. Vaccines that target determinants conserved among influenza A viruses (IAV) to generate broad protection against infection with different influenza A subtypes (i.e., heterosubtypic immunity [HSI]) remain elusive. We have currently developed a recombinant adenovirus (Ad) vector co-encoding HA (H5 subtype) and a conserved ectodomain of matrix protein 2 (M2e) (AdH5/M2e) for induction of protective immunity to H5N1 and other subtypes. Another approach based on the use of influenza virus carrying a deletion in the nonstructural NS1 gene is being explored. Since NS1 enables the virus to disarm the host type 1 IFN response, such deletion leads to attenuation of the viruses and enhanced host antiviral response. Therefore, vaccines based on NS1 deleted viruses (DelNS1) may provide better protection than inactivated vaccines and could induce HSI to infection with different influenza virus A subtypes. Sub-lingual immunization has been found to be a safe and effective route for induction of protective immune responses in systemic and mucosal compartments including respiratory tract. We found that sublingual immunization with either AdH5/M2e or DelNS1 induces broad protective immunity to H5 viruses and other influenza virus A subtypes including H1N1. Passive immunization (the transfer of specific immunoglobulins/Abs to a previously nonimmune recipient host) could offer an alternative strategy to prevent and treat influenza virus infection and an additional therapeutic option to antiviral drugs that are limited by widespread drug resistance among influenza virus strains. Even after targeted vaccines become available, passive immunization could still have prophylactic effects and provides an additional countermeasure against influenza, especially for individuals who do not respond well to the vaccines. Attempts to develop monoclonal Abs (mAbs) have been made. However, passive immunization based on mAbs may require a cocktail of mAbs with broader specificity in order to provide full protection since mAbs are generally specific for single epitopes. Because the recent epidemic of highly pathogenic avian