Stopping emerging influenza viruses at their origin
Authors: Florian Krammer
Journal: The Lancet Infectious Diseases (2017)

During the past 100 years, two of four influenza virus pandemics originated in Asia. Additionally, many of the emerging influenza viruses that are deemed to have pandemic potential, including H5N1, H5N6, H6N1, H7N9, and H10N8, have crossed the species barrier from animals to human beings in Asia.1Lai S Qin Y Cowling BJ et al.Global epidemiology of avian influenza A H5N1 virus infection in humans, 1997–2015: a systematic review of individual case data.Lancet Infect Dis. 2016; 16: e108-e118Summary Full Text Full Text PDF PubMed Scopus (157) Google Scholar, 2Palese P Influenza: old and new threats.Nat Med. 2004; 10: S82-S87Crossref PubMed Scopus (483) Google Scholar, 3Jiang H Wu P Uyeki TM et al.Preliminary epidemiologic assessment of human infections with highly pathogenic avian influenza A(H5N6) virus, China.Clin Infect Dis. 2017; (published online April 12)https://doi.org/10.1093/cid/cix334Crossref Scopus (52) Google Scholar, 4Zhang F Bi Y Wang J et al.Human infections with recently-emerging highly pathogenic H7N9 avian influenza virus in China.J Infect. 2017; (published online April 6)https://doi.org/10.1016/j.jinf.2017.04.001Summary Full Text Full Text PDF Scopus (119) Google Scholar, 5Chen H Yuan H Gao R et al.Clinical and epidemiological characteristics of a fatal case of avian influenza A H10N8 virus infection: a descriptive study.Lancet. 2014; 383: 714-721Summary Full Text Full Text PDF PubMed Scopus (459) Google Scholar, 6Shi W Shi Y Wu Y Liu D Gao GF Origin and molecular characterization of the human-infecting H6N1 influenza virus in Taiwan.Protein Cell. 2013; 4: 846-853Crossref PubMed Scopus (73) Google Scholar One reason for this might be the extensive interface between human beings, domestic poultry, and wild waterfowl, which is generated by the high human population density, the high density of domestic poultry, and ample opportunities for domestic birds to be exposed to wild waterfowl in some regions of Asia. This environment provides avian influenza viruses with the opportunity to evolve, reassort, and, ultimately, infect human beings. Although zoonotic infections might have high case-fatality rates, it is unlikely that a fully avian virus will cause the next pandemic. However, a higher number of zoonotic infections results in a higher chance of co-infection of human beings with avian and seasonal human viruses. Reassortants resulting from these co-infections might have substantial pandemic potential. In a study in The Lancet Infectious Diseases, Punnee Pitisuttithum and colleagues7Pitisuttithum P Boonnak K Chamnanchanunt S et al.Safety and immunogenicity of a live attenuated influenza H5 candidate vaccine strain A/17/turkey/Turkey/05/133 H5N2 and its priming effects for potential pre-pandemic use: a randomised, double-blind, placebo-controlled trial.Lancet Infect Dis. 2017; (published online May 19.)http://dx.doi.org/10.1016/S1473-3099(17)30240-2PubMed Google Scholar describe a major step forward towards better pandemic preparedness in low-income and middle-income countries. Efforts to create vaccines against avian influenza viruses of concern have mainly focused on H5 and H7 viruses. These vaccines are considered to be poorly immunogenic in human beings, particularly if the traditional correlate of protection, the haemagglutination-inhibition titre, is used.8Luke CJ Subbarao K Improving pandemic H5N1 influenza vaccines by combining different vaccine platforms.Expert Rev Vaccines. 2014; 13: 873-883Crossref PubMed Scopus (27) Google Scholar One way to overcome this poor immunogenicity is to use heterologous prime–boost vaccine regimens, in which a prime is given in the form of a live-attenuated influenza virus vaccine (LAIV) and a boost is given as an inactivated influenza virus vaccine (IIV). In a landmark paper in 2014,9Talaat KR Luke CJ Khurana S et al.A live attenuated influenza A(H5N1) vaccine induces long-term immunity in the absence of a primary antibody response.J Infect Dis. 2014; 209: 1860-1869Crossref PubMed Scopus (83) Google Scholar the immune response to H5 haemagglutinin was shown to be boosted when an IIV is given after LAIV even in the absence of a strong primary response to the LAIV component. The immunity induced by the heterologous prime–boost regimen proved to be very robust and broad, spanning several clades of H5N1 viruses, and clearly outperforming the standard vaccine regimen of giving IIV twice in a short interval. These findings have sparked hope that a heterologous prime–boost vaccination regimen could become an effective tool to protect from emerging influenza viruses.9Talaat KR Luke CJ Khurana S et al.A live attenuated influenza A(H5N1) vaccine induces long-term immunity in the absence of a primary antibody response.J Infect Dis. 2014; 209: 1860-1869Crossref PubMed Scopus (83) Google Scholar Major efforts are under way to establish capacity to produce influenza virus vaccine in low-income and middle-income countries.10Wahid R Holt R Hjorth R Berlanda Scorza F Chemistry, manufacturing and control (CMC) and clinical trial technical support for influenza vaccine manufacturers.Vaccine. 2016; 34: 5430-5435Crossref PubMed Scopus (6) Google Scholar Such capacity would enable the local production of vaccines in response to a novel influenza pandemic or might even help to prevent pandemics by containing local outbreaks. Punnee Pitisuttithum and colleagues7Pitisuttithum P Boonnak K Chamnanchanunt S et al.Safety and immunogenicity of a live attenuated influenza H5 candidate vaccine strain A/17/turkey/Turkey/05/133 H5N2 and its priming effects for potential pre-pandemic use: a randomised, double-blind, placebo-controlled trial.Lancet Infect Dis. 2017; (published online May 19.)http://dx.doi.org/10.1016/S1473-3099(17)30240-2PubMed Google Scholar report the results of a clinical trial that tested an H5 LAIV–IIV vaccination regimen in Thailand. This trial was made possible by a collaboration between Mahidol University, which did the trial, the Governmental Pharmaceutical Organization of Thailand, which locally produced the LAIV, the Institute of Experimental Medicine in St Petersburg, Russia, which provided the LAIV seed virus,11Isakova-Sivak I Tretiak T Rudenko L Cold-adapted influenza viruses as a promising platform for viral-vector vaccines.Expert Rev Vaccines. 2016; 15: 1241-1243Crossref PubMed Scopus (17) Google Scholar WHO, and several other partners including the US Biomedical Advanced Research and Development Authority, which provided funding through WHO. Although the LAIV donor strain and the H5 haemagglutinin of the vaccine were different from the ones used in the 2014 US study,7Pitisuttithum P Boonnak K Chamnanchanunt S et al.Safety and immunogenicity of a live attenuated influenza H5 candidate vaccine strain A/17/turkey/Turkey/05/133 H5N2 and its priming effects for potential pre-pandemic use: a randomised, double-blind, placebo-controlled trial.Lancet Infect Dis. 2017; (published online May 19.)http://dx.doi.org/10.1016/S1473-3099(17)30240-2PubMed Google Scholar, 9Talaat KR Luke CJ Khurana S et al.A live attenuated influenza A(H5N1) vaccine induces long-term immunity in the absence of a primary antibody response.J Infect Dis. 2014; 209: 1860-1869Crossref PubMed Scopus (83) Google Scholar the results and conclusions are the same: vaccination with an H5 LAIV followed by an H5 IIV induces robust and broad antibody responses against H5N1 viruses. The outcome of this study proves that it is feasible to transfer this highly valuable vaccine concept to low-income and middle-income country settings. The study also raises several questions: how will this vaccine strategy be tested in phase 2 and 3 clinical trials? The LAIV was administered to vaccinees in an isolation unit to prevent reassortment of the LAIV strain with circulating human influenza viruses. A reassortment event could lead to a new virus perfectly adapted to human beings, but carrying an H5 haemagglutinin to which human beings are naive. Will all LAIV vaccinations have to be done in isolation units in future trials? Is that feasible? And what is the risk of reassortment? Are there technologies that could reduce the risk involved with this approach? How will the vaccine be used in the field once approved? Would it make sense, and would it be ethical, to prime, or even fully vaccinate, local health-care personnel, public safety personnel, and essential community personnel in anticipation of an H5 pandemic? Could priming (or even full vaccination) of the local at-risk population, including individuals in close contact with poultry, help to reduce the risk of a novel pandemic? Although there are many open questions, it is clear that the LAIV–IIV prime–boost approach could become a powerful tool to enhance global pandemic preparedness against H5N1 and other influenza virus strains of concern. My research group is working on the design of influenza virus vaccines and my institution has patent applications on influenza virus vaccines pending. Safety and immunogenicity of a live attenuated influenza H5 candidate vaccine strain A/17/turkey/Turkey/05/133 H5N2 and its priming effects for potential pre-pandemic use: a randomised, double-blind, placebo-controlled trialOur data suggest that LAIV vaccination induces long-lasting memory immune responses. The limitation of this study was that part 2 was designed as a proof-of-concept study by contrast with part 1. Full-Text PDF Open Access