Influenza is a perennial problem affecting millions of people annually with the everpresent threat of devastating pandemics. Active prophylaxis by vaccination against influenza virus is currently the main countermeasure supplemented with antivirals. However, disadvantages of this strategy include the impact of antigenic drift, necessitating constant updating of vaccine strain composition, and emerging antiviral drug resistance. The development of other options for influenza prophylaxis, particularly with broad acting agents able to provide protection in the period between the onset of a pandemic and the development of a strain specific vaccine, is of great interest. Exploitation of broad-spectrum mediators could provide barricade protection in the early critical phase of influenza virus outbreaks. Passive immunity has the potential to provide immediate antiviral effects, inhibiting virus replication, reducing virus shedding, and thereby protecting vulnerable populations in the event of an impending influenza pandemic. Here, we review passive broad-spectrum influenza prophylaxis options with a focus on harnessing natural host defenses, including interferons and antibodies. 1. Introduction Seasonal influenza causes serious disease burden, particularly in children and the elderly, with the need to develop annual vaccines based on predicted circulating strains due to antigenic drift of the virus. Furthermore, newly emerging novel influenza A viruses pose a significant threat of a pandemic with potentially devastating consequences [1]. Moreover, as pandemic strain vaccines require time for development and deployment, virus replication and spread are initially unchecked allowing the outbreak to gain momentum. Currently, vaccines and antivirals are used for control of influenza but emerging virus resistance to these measures presents limitations. Furthermore, as antiviral drugs could not be stockpiled in sufficient amounts for global supply, alternative control measures need to be urgently considered. A potential solution lies in the development of a universal vaccine based on conserved viral epitopes that induces cross-reactive antibodies that neutralize variant viruses from within a subtype and protects against heterologous viruses. Therefore, whilst existing vaccines are inadequate for cross protection and a universal vaccine may be difficult to achieve, it is both pertinent and timely to consider other possible broad-spectrum options, particularly as different virus subtypes not previously experienced by humans are emerging and have pandemic potential. In
References
[1]
J. K. Taubenberger and D. M. Morens, “Pandemic influenza—including a risk assessment of H5N1,” Revue Scientifique et Technique, vol. 28, no. 1, pp. 187–202, 2009.
[2]
R. Salomon and R. G. Webster, “The influenza virus enigma,” Cell, vol. 136, no. 3, pp. 402–410, 2009.
[3]
G. N. Rogers and J. C. Paulson, “Receptor determinants of human and animal influenza virus isolates: differences in receptor specificity of the H3 hemagglutinin based on species of origin,” Virology, vol. 127, no. 2, pp. 361–373, 1983.
J. K. Taubenberger and D. M. Morens, “1918 Influenza: the mother of all pandemics,” Emerging Infectious Diseases, vol. 12, no. 1, pp. 15–22, 2006.
[7]
CDC, “Swine influenza A (H1N1) infection in two children-Southern California, March-April 2009,” Morbidity Mortality Weekly Report, vol. 58, pp. 400–402, 2009.
[8]
M. Imai, T. Watanabe, M. Hatta et al., “Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets,” Nature, vol. 486, no. 7403, pp. 420–428, 2012.
[9]
J. A. McCullers, “The co-pathogenesis of influenza viruses with bacteria in the lung,” Nature Reviews Microbiology, vol. 12, no. 4, pp. 252–262, 2014.
[10]
C. J. Sanders, P. C. Doherty, and P. G. Thomas, “Respiratory epithelial cells in innate immunity to influenza virus infection,” Cell and Tissue Research, vol. 343, no. 1, pp. 13–21, 2011.
[11]
K. R. Short, E. J. Kroeze, R. A. Fouchier, and T. Kuiken, “Pathogenesis of influenza-induced acute respiratory distress syndrome,” The Lancet Infectious Diseases, vol. 14, no. 1, pp. 57–69, 2014.
[12]
F. G. Hayden, R. S. Fritz, M. C. Lobo, W. G. Alvord, W. Strober, and S. E. Straus, “Local and systemic cytokine responses during experimental human influenza A virus infection. Relation to symptom formation and host defense,” The Journal of Clinical Investigation, vol. 101, no. 3, pp. 643–649, 1998.
[13]
K. Subbarao, B. R. Murphy, and A. S. Fauci, “Development of effective vaccines against pandemic influenza,” Immunity, vol. 24, no. 1, pp. 5–9, 2006.
[14]
C.-Y. Wu, Y.-C. Yeh, J.-T. Chan et al., “A VLP vaccine induces broad-spectrum cross-protective antibody immunity against H5N1 and H1N1 subtypes of influenza A virus,” PLoS ONE, vol. 7, no. 8, Article ID e42363, 2012.
[15]
N. Yamane, Y. Nakamura, M. Yuki, T. Odagiri, and N. Ishida, “Serological evaluation of an influenza A virus cold-adapted reassortant live vaccine, CR-37 (H1N1), in Japanese adult volunteers,” Journal of Hygiene, vol. 92, no. 2, pp. 231–242, 1984.
[16]
R. Levi and R. Arnon, “Synthetic recombinant influenza vaccine induces efficient long-term immunity and cross-strain protection,” Vaccine, vol. 14, no. 1, pp. 85–92, 1996.
[17]
S. Neirynck, T. Deroo, X. Saelens, P. Vanlandschoot, W. M. Jou, and W. Fiers, “A universal influenza A vaccine based on the extracellular domain of the M2 protein,” Nature Medicine, vol. 5, no. 10, pp. 1157–1163, 1999.
[18]
A. Takada, S. Matsushita, A. Ninomiya, Y. Kawaoka, and H. Kida, “Intranasal immunization with formalin-inactivated virus vaccine induces a broad spectrum of heterosubtypic immunity against influenza A virus infection in mice,” Vaccine, vol. 21, no. 23, pp. 3212–3218, 2003.
[19]
D. Corti, A. L. Suguitan Jr., D. Pinna et al., “Heterosubtypic neutralizing antibodies are produced by individuals immunized with a seasonal influenza vaccine,” The Journal of Clinical Investigation, vol. 120, no. 5, pp. 1663–1673, 2010.
[20]
A. C. Hurt, “The epidemiology and spread of drug resistant human influenza viruses,” Current Opinion in Virology, vol. 8, pp. 22–29, 2014.
[21]
B. R. O'Keefe, D. F. Smee, J. A. Turpin et al., “Potent anti-influenza activity of cyanovirin-N and interactions with viral hemagglutinin,” Antimicrobial Agents and Chemotherapy, vol. 47, no. 8, pp. 2518–2525, 2003.
[22]
Y. Furuta, B. B. Gowen, K. Takahashi, K. Shiraki, D. F. Smee, and D. L. Barnard, “Favipiravir (T-705), a novel viral RNA polymerase inhibitor,” Antiviral Research, vol. 100, no. 2, pp. 446–454, 2013.
[23]
K. Das, “Antivirals targeting influenza a virus,” Journal of Medicinal Chemistry, vol. 55, no. 14, pp. 6263–6277, 2012.
[24]
R. W. Y. Chan, M. C. W. Chan, A. C. N. Wong, et al., “DAS181 inhibits H5N1 influenza virus infection of human lung tissues,” Antimicrobial Agents and Chemotherapy, vol. 53, no. 9, pp. 3935–3941, 2009.
[25]
T. Gong, Y. Jiang, Y. Wang, et al., “Recombinant mouse beta-defensin 2 inhibits infection by influenza A virus by blocking its entry,” Archives of Virology, vol. 155, no. 4, pp. 491–498, 2010.
[26]
Y.-F. Lau, L.-H. Tang, and E.-E. Ooi, “A TLR3 ligand that exhibits potent inhibition of influenza virus replication and has strong adjuvant activity has the potential for dual applications in an influenza pandemic,” Vaccine, vol. 27, no. 9, pp. 1354–1364, 2009.
[27]
K. A. Shirey, W. Lai, A. J. Scott et al., “The TLR4 antagonist Eritoran protects mice from lethal influenza infection,” Nature, vol. 497, no. 7450, pp. 498–502, 2013.
[28]
Y. Li, Y. Hu, Y. Jin et al., “Prophylactic, therapeutic and immune enhancement effect of liposome-encapsulated PolyICLC on highly pathogenic H5N1 influenza infection,” The Journal of Gene Medicine, vol. 13, no. 1, pp. 60–72, 2011.
[29]
L. Lin, Q. Liu, N. Berube, S. Detmer, and Y. Zhou, “5′-Triphosphate-short interfering RNA: potent inhibition of influenza a virus infection by gene silencing and RIG-I activation,” Journal of Virology, vol. 86, no. 19, pp. 10359–10369, 2012.
[30]
G. J. Kotwal, “Genetic diversity-independent neutralization of pandemic viruses (e.g. HIV), potentially pandemic (e.g. H5N1 strain of influenza) and carcinogenic (e.g. HBV and HCV) viruses and possible agents of bioterrorism (variola) by enveloped virus neutralizing compounds (EVNCs),” Vaccine, vol. 26, no. 24, pp. 3055–3058, 2008.
[31]
W.-J. Shin, Y.-K. Kim, K.-H. Lee, and B.-L. Seong, “Evaluation of the antiviral activity of a green tea solution as a hand-wash disinfectant,” Bioscience, Biotechnology and Biochemistry, vol. 76, no. 3, pp. 581–584, 2012.
[32]
Q. Li, Z. Zhao, D. Zhou et al., “Virucidal activity of a scorpion venom peptide variant mucroporin-M1 against measles, SARS-CoV and influenza H5N1 viruses,” Peptides, vol. 32, no. 7, pp. 1518–1525, 2011.
[33]
S. A. Samarajiwa, S. Forster, K. Auchettl, and P. J. Hertzog, “INTERFEROME: the database of interferon regulated genes,” Nucleic Acids Research, vol. 37, supplement 1, pp. D852–D857, 2009.
[34]
L. A. Durfee and J. M. Huibregtse, “Identification and validation of ISG15 target proteins,” Subcellular Biochemistry, vol. 54, pp. 228–237, 2010.
[35]
R. H. Silverman and S. R. Weiss, “Viral phosphodiesterases that antagonize double-stranded RNA signaling to RNase L by degrading 2-5A,” Journal of Interferon and Cytokine Research, vol. 34, pp. 455–463, 2014.
[36]
D. Rebouillat and A. G. Hovanessian, “The human 2′,5′-oligoadenylate synthetase family: interferon-induced proteins with unique enzymatic properties,” Journal of Interferon and Cytokine Research, vol. 19, no. 4, pp. 295–308, 1999.
[37]
O. Haller, G. Kochs, and F. Weber, “Interferon, Mx, and viral countermeasures,” Cytokine and Growth Factor Reviews, vol. 18, no. 5-6, pp. 425–433, 2007.
[38]
E. Baig and E. N. Fish, “Distinct signature type I interferon responses are determined by the infecting virus and the target cell,” Antiviral Therapy, vol. 13, no. 3, pp. 409–422, 2008.
[39]
L. M. Pfeffer, C. A. Dinarello, R. B. Herberman et al., “Biological properties of recombinant α-interferons: 40th anniversary of the discovery of interferons,” Cancer Research, vol. 58, no. 12, pp. 2489–2499, 1998.
[40]
G. Kochs, A. García-Sastre, and L. Martínez-Sobrido, “Multiple anti-interferon actions of the influenza A virus NS1 protein,” Journal of Virology, vol. 81, no. 13, pp. 7011–7021, 2007.
[41]
Y.-F. Lau, L.-H. Tang, E.-E. Ooi, and K. Subbarao, “Activation of the innate immune system provides broad-spectrum protection against influenza A viruses with pandemic potential in mice,” Virology, vol. 406, no. 1, pp. 80–87, 2010.
[42]
K. S. Tan, F. Olfat, M. C. Phoon et al., “In vivo and in vitro studies on the antiviral activities of viperin against influenza H1N1 virus infection,” Journal of General Virology, vol. 93, no. 6, pp. 1269–1277, 2012.
[43]
C. M. James, M. Y. Abdad, J. P. Mansfield et al., “Differential activities of alpha/beta IFN subtypes against influenza virus in vivo and enhancement of specific immune responses in DNA vaccinated mice expressing haemagglutinin and nucleoprotein,” Vaccine, vol. 25, no. 10, pp. 1856–1867, 2007.
[44]
J.-K. Yoo, D. P. Baker, and E. N. Fish, “Interferon-β modulates type 1 immunity during influenza virus infection,” Antiviral Research, vol. 88, no. 1, pp. 64–71, 2010.
[45]
U. R. Malik, D. F. Makower, and S. Wadler, “Interferon-mediated fatigue,” Cancer, vol. 92, no. 6 supplement, pp. 1664–1668, 2001.
[46]
R. G. Thorne, L. R. Hanson, T. M. Ross, D. Tung, and W. H. Frey II, “Delivery of interferon-β to the monkey nervous system following intranasal administration,” Neuroscience, vol. 152, no. 3, pp. 785–797, 2008.
[47]
A. D. Brideau-Andersen, X. Huang, S.-C. C. Sun et al., “Directed evolution of gene-shuffled IFN-α molecules with activity profiles tailored for treatment of chronic viral diseases,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 20, pp. 8269–8274, 2007.
[48]
A. L. Bennett, D. W. Smith, M. J. Cummins, P. A. Jacoby, J. M. Cummins, and M. W. Beilharz, “Low-dose oral interferon alpha as prophylaxis against viral respiratory illness: a double-blind, parallel controlled trial during an influenza pandemic year,” Influenza and other Respiratory Viruses, vol. 7, no. 5, pp. 854–862, 2013.
[49]
J. Wang, R. Oberley-Deegan, S. Wang et al., “Differentiated human alveolar type II cells secrete antiviral IL-29 (IFN-λ1) in response to influenza a infection,” The Journal of Immunology, vol. 182, no. 3, pp. 1296–1304, 2009.
[50]
M. Mordstein, E. Neugebauer, V. Ditt et al., “Lambda interferon renders epithelial cells of the respiratory and gastrointestinal tracts resistant to viral infections,” Journal of Virology, vol. 84, no. 11, pp. 5670–5677, 2010.
[51]
R. K. Durbin, S. V. Kotenko, and J. E. Durbin, “Interferon induction and function at the mucosal surface,” Immunological Reviews, vol. 255, no. 1, pp. 25–39, 2013.
[52]
J. S. M. Peiris, C. Y. Cheung, C. Y. H. Leung, and J. M. Nicholls, “Innate immune responses to influenza A H5N1: friend or foe?” Trends in Immunology, vol. 30, no. 12, pp. 574–584, 2009.
[53]
J. R. Teijaro, K. B. Walsh, S. Cahalan, et al., “Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection,” Cell, vol. 146, no. 6, pp. 980–991, 2011.
[54]
A. Iwasaki and R. Medzhitov, “Regulation of adaptive immunity by the innate immune system,” Science, vol. 327, no. 5963, pp. 291–295, 2010.
[55]
E. E. Waffarn and N. Baumgarth, “Protective B cell responses to Flu-No fluke!,” Journal of Immunology, vol. 186, no. 7, pp. 3823–3829, 2011.
[56]
S. A. Plotkin, “Correlates of vaccine-induced immunity,” Clinical Infectious Diseases, vol. 47, no. 3, pp. 401–409, 2008.
[57]
A. Sundararajan, L. Huan, K. A. Richards et al., “Host differences in influenza-specific CD4 T cell and B cell responses are modulated by viral strain and route of immunization,” PLoS ONE, vol. 7, no. 3, Article ID e34377, 2012.
[58]
C. C. Goodnow, C. G. Vinuesa, K. L. Randall, F. MacKay, and R. Brink, “Control systems and decision making for antibody production,” Nature Immunology, vol. 11, no. 8, pp. 681–688, 2010.
[59]
J. H. Beigel and T. C. Luke, “A study in scarlet-convalescent plasma for severe influenza,” Critical Care Medicine, vol. 40, no. 3, pp. 1027–1028, 2012.
[60]
J. Ye, H. Shao, and D. R. Perez, “Passive immune neutralization strategies for prevention and control of influenza A infections,” Immunotherapy, vol. 4, no. 2, pp. 175–186, 2012.
[61]
S. ？kerfeldt, S. Geijer, E. Holubars, G. Fuchs, and M. Brundin, “Prophylactic and therapeutic antiviral effect of human gamma globulin,” Biochemical Pharmacology, vol. 21, no. 4, pp. 503–509, 1972.
[62]
F. Ramisse, F.-X. Deramoudt, M. Szatanik et al., “Effective prophylaxis of influenza A virus pneumonia in mice by topical passive immunotherapy with polyvalent human immunoglobulins or F(ab')2 fragments,” Clinical and Experimental Immunology, vol. 111, no. 3, pp. 583–587, 1998.
[63]
T. C. Luke, A. Casadevall, S. J. Watowich, S. L. Hoffman, J. H. Beigel, and T. H. Burgess, “Hark back: passive immunotherapy for influenza and other serious infections,” Critical Care Medicine, vol. 38, no. 4, pp. e66–e73, 2010.
[64]
B. Zhou, N. Zhong, and Y. Guan, “Treatment with convalescent plasma for influenza A (H5N1) infection,” The New England Journal of Medicine, vol. 357, no. 14, pp. 1450–1451, 2007.
[65]
I. F. N. Hung, K. K. W. To, C.-K. Lee, et al., “Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection,” Clinical Infectious Diseases, vol. 52, no. 4, pp. 447–456, 2011.
[66]
S. Rockman, D. Maher, and D. Middleton, “The use of hyperimmune serum for severe influenza infections,” Critical Care Medicine, vol. 40, no. 3, pp. 973–975, 2012.
[67]
W. C. Ng, V. Wong, B. Muller, G. Rawlin, and L. E. Brown, “Prevention and treatment of influenza with hyperimmune bovine colostrum antibody,” PLoS One, vol. 5, no. 10, Article ID e13622, 2010.
[68]
D. C. Ekiert, G. Bhabha, M.-A. Elsliger et al., “Antibody recognition of a highly conserved influenza virus epitope,” Science, vol. 324, no. 5924, pp. 246–251, 2009.
[69]
D. J. Dilillo, G. S. Tan, P. Palese, and J. V. Ravetch, “Broadly neutralizing hemagglutinin stalk-specific antibodies require FcR interactions for protection against influenza virus in vivo,” Nature Medicine, vol. 20, no. 2, pp. 143–151, 2014.
[70]
N. Pica, R. Hai, F. Krammer et al., “Hemagglutinin stalk antibodies elicited by the 2009 pandemic influenza virus as a mechanism for the extinction of seasonal H1N1 viruses,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 7, pp. 2573–2578, 2012.
[71]
H. Zhang, L. Wang, R. W. Compans, and B.-Z. Wang, “Universal influenza vaccines, a dream to be realized soon,” Viruses, vol. 6, no. 5, pp. 1974–1991, 2014.
[72]
N. S. Laursen and I. A. Wilson, “Broadly neutralizing antibodies against influenza viruses,” Antiviral Research, vol. 98, no. 3, pp. 476–483, 2013.
[73]
M. Throsby, E. van den Brink, M. Jongeneelen, et al., “Heterosubtypic neutralizing monoclonal antibodies cross-protective against H5N1 and H1N1 recovered from human IgM+ memory B cells,” PLoS ONE, vol. 3, no. 12, Article ID e3942, 2008.
[74]
R. H. E. Friesen, W. Koudstaal, M. H. Koldijk et al., “New class of monoclonal antibodies against severe influenza: Prophylactic and therapeutic efficacy in ferrets,” PLoS ONE, vol. 5, no. 2, Article ID e9106, 2010.
[75]
K. Hancock, V. Veguilla, X. Lu et al., “Cross-reactive antibody responses to the 2009 pandemic H1N1 influenza virus,” The New England Journal of Medicine, vol. 361, no. 20, pp. 1945–1952, 2009.
[76]
W. Koudstaal, M. H. Koldijk, J. P. J. Brakenhoff et al., “Pre- and postexposure use of human monoclonal antibody against H5N1 and H1N1 influenza virus in mice: viable alternative to oseltamivir,” Journal of Infectious Diseases, vol. 200, no. 12, pp. 1870–1873, 2009.
[77]
Q. Zheng, L. Xia, W. L. Wu et al., “Properties and therapeutic efficacy of broadly reactive chimeric and humanized H5-specific monoclonal antibodies against H5N1 influenza viruses,” Antimicrobial Agents and Chemotherapy, vol. 55, no. 4, pp. 1349–1357, 2011.
[78]
S. Sakabe, K. Iwatsuki-Horimoto, T. Horimoto et al., “A cross-reactive neutralizing monoclonal antibody protects mice from H5N1 and pandemic (H1N1) 2009 virus infection,” Antiviral Research, vol. 88, no. 3, pp. 249–255, 2010.
[79]
J. S. Shin, H. S. Kim, S. H. Cho, and S. H. Seo, “IgG antibodies mediate protective immunity of inactivated vaccine for highly pathogenic H5N1 influenza viruses in ferrets,” Viral Immunology, vol. 23, no. 3, pp. 321–327, 2010.
[80]
J. Alisky, “Bovine and human-derived passive immunization could help slow a future avian influenza pandemic,” Medical Hypotheses, vol. 72, no. 1, pp. 74–75, 2009.
[81]
Z. Zhao, F. Yan, Z. Chen et al., “Cross clade prophylactic and therapeutic efficacy of polyvalent equine immunoglobulin F(ab′)2 against highly pathogenic avian influenza H5N1 in mice,” International Immunopharmacology, vol. 11, no. 12, pp. 2000–2006, 2011.
[82]
I. Margine, R. Hai, R. A. Albrecht et al., “H3N2 influenza virus infection induces broadly reactive hemagglutinin stalk antibodies in humans and mice,” Journal of Virology, vol. 87, no. 8, pp. 4728–4737, 2013.
[83]
I. Margine, F. Krammer, R. Hai et al., “Hemagglutinin stalk-based universal vaccine constructs protect against group 2 influenza A viruses,” Journal of Virology, vol. 87, no. 19, pp. 10435–10446, 2013.
[84]
C. J. Wei, J. C. Boyington, P. M. McTamney et al., “Induction of broadly neutralizing H1N1 influenza antibodies by vaccination,” Science, vol. 329, no. 5995, pp. 1060–1064, 2010.
[85]
F. Krammer and P. Palese, “Universal influenza virus vaccines: need for clinical trials,” Nature Immunology, vol. 15, no. 1, pp. 3–5, 2014.
[86]
R. M. Kris, R. A. Yetter, R. Cogliano, R. Ramphal, and P. A. Small, “Passive serum antibody causes temporary recovery from influenza virus infection of the nose, trachea and lung of nude mice,” Immunology, vol. 63, no. 3, pp. 349–353, 1988.
[87]
J. P. Wong, L. L. Stadnyk, and E. G. Saravolac, “Enhanced protection against respiratory influenza A infection in mice by liposome-encapsulated antibody,” Immunology, vol. 81, no. 2, pp. 280–284, 1994.
[88]
C. Dreffier, F. Ramisse, and C. Dubernet, “Pulmonary administration of IgG loaded liposomes for passive immunoprophylaxy,” International Journal of Pharmaceutics, vol. 254, no. 1, pp. 43–47, 2003.
[89]
A. I. Bot, T. E. Tarara, D. J. Smith, S. R. Bot, C. M. Woods, and J. G. Weers, “Novel lipid-based hollow-porous microparticles as a platform for immunoglobulin delivery to the respiratory tract,” Pharmaceutical Research, vol. 17, no. 3, pp. 275–283, 2000.
[90]
G. J. Milne, N. Halder, and J. K. Kelso, “The cost effectiveness of pandemic influenza interventions: a pandemic severity based analysis,” PLoS ONE, vol. 8, no. 4, Article ID e61504, 2013.
[91]
L. E. Richert, A. Rynda-Apple, A. L. Harmsen et al., “CD11c+ cells primed with unrelated antigens facilitate an accelerated immune response to influenza virus in mice,” European Journal of Immunology, vol. 44, no. 2, pp. 397–408, 2014.
[92]
N. Clementi, E. Criscuolo, M. Castelli, N. Mancini, M. Clementi, and R. Burioni, “Influenza B-cells protective epitope characterization: a passkey for the rational design of new broad-range anti-influenza vaccines,” Viruses, vol. 4, no. 11, pp. 3090–3108, 2012.
[93]
F. Krammer, R. Hai, M. Yondola et al., “Assessment of influenza virus hemagglutinin stalk-based immunity in ferrets,” Journal of Virology, vol. 88, no. 6, pp. 3432–3442, 2014.
[94]
J. L. Goodman, “Studying “secret serums”—toward safe, effective Ebola treatments,” The New England Journal of Medicine, 2014.
[95]
C. Rinaldi, W. J. Penhale, P. A. Stumbles, G. Tay, and C. M. Berry, “Modulation of innate immune responses by influenza-specific ovine polyclonal antibodies used for prophylaxis,” PLoS ONE, vol. 9, no. 2, Article ID e89674, 2014.
[96]
T. M. Uyeki, “Preventing and controlling influenza with available interventions,” The New England Journal of Medicine, vol. 370, no. 9, pp. 789–791, 2014.
[97]
R. G. Webster, “Original antigenic sin in ferrets: the response to sequential infections with influenza viruses,” The Journal of Immunology, vol. 97, no. 2, pp. 177–183, 1966.
[98]
J. H. Kim, I. Skountzou, R. Compans, and J. Jacob, “Original antigenic sin responses to influenza viruses,” Journal of Immunology, vol. 183, no. 5, pp. 3294–3301, 2009.
