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Dr. Jefferson Santos
Department of Population Health, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20852, USA

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0 Vaccines
0 B cells
0 Reverse genetics
0 Influenza viruses
0 immunological memory

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Journal article
Published: 30 June 2021 in Viruses
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Influenza B viruses (IBV) circulate annually, with young children, the elderly and immunocompromised individuals being at high risk. Yearly vaccinations are recommended to protect against seasonally influenza viruses, including IBV. Live attenuated influenza vaccines (LAIV) provide the unique opportunity for direct exposure to the antigenically variable surface glycoproteins as well as the more conserved internal components. Ideally, LAIV Master Donor Viruses (MDV) should accurately reflect seasonal influenza strains. Unfortunately, the continuous evolution of IBV have led to significant changes in conserved epitopes compared to the IBV MDV based on B/Ann Arbor/1/1966 strain. Here, we propose a recent influenza B/Brisbane/60/2008 as an efficacious MDV alternative, as its internal viral proteins more accurately reflect those of circulating IBV strains. We introduced the mutations responsible for the temperature sensitive (ts), cold adapted (ca) and attenuated (att) phenotype of B/Ann Arbor/1/1966 MDV LAIV into B/Brisbane/60/2008 to generate a new MDV LAIV. In vitro and in vivo analysis demonstrated that the mutations responsible of the ts, ca, and att phenotype of B/Ann Arbor/1/1966 MDV LAIV were able to infer the same phenotype to B/Brisbane/60/2008, demonstrating its potential as a new MDV for the development of LAIV to protect against contemporary IBV strains.

ACS Style

Chantelle White; Kevin Chiem; Daniel Perez; Jefferson Santos; Stivalis Cardenas Garcia; Aitor Nogales; Luis Martínez-Sobrido. A New Master Donor Virus for the Development of Live-Attenuated Influenza B Virus Vaccines. Viruses 2021, 13, 1278 .

AMA Style

Chantelle White, Kevin Chiem, Daniel Perez, Jefferson Santos, Stivalis Cardenas Garcia, Aitor Nogales, Luis Martínez-Sobrido. A New Master Donor Virus for the Development of Live-Attenuated Influenza B Virus Vaccines. Viruses. 2021; 13 (7):1278.

Chicago/Turabian Style

Chantelle White; Kevin Chiem; Daniel Perez; Jefferson Santos; Stivalis Cardenas Garcia; Aitor Nogales; Luis Martínez-Sobrido. 2021. "A New Master Donor Virus for the Development of Live-Attenuated Influenza B Virus Vaccines." Viruses 13, no. 7: 1278.

Journal article
Published: 21 January 2020 in Cold Spring Harbor Perspectives in Medicine
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We review the phenomenon of “original antigenic sin” (OAS) in antibody responses to influenza A virus (IAV) infection or vaccination. OAS refers to the preferential induction of antibodies with higher affinity to priming versus boosting immunogens. We emphasize its mechanistic basis and origins in the basic immunobiology of B-cell responses to myriad immunogens. We tabulate 23 studies in animals and humans to show that the magnitude of OAS depends on many variables. We discuss a number of misconceptions about OAS, examine the extent to which OAS is sinful, and argue that OAS is evolutionary selected and not a deleterious by-product of selection for other features of the immune response. We end by raising questions regarding the mechanistic basis of OAS whose answers could contribute to improving influenza virus vaccines on the road to the holy grail of a “universal” influenza vaccine.

ACS Style

Jonathan W. Yewdell; Jefferson Santos. Original Antigenic Sin: How Original? How Sinful? Cold Spring Harbor Perspectives in Medicine 2020, 11, a038786 .

AMA Style

Jonathan W. Yewdell, Jefferson Santos. Original Antigenic Sin: How Original? How Sinful? Cold Spring Harbor Perspectives in Medicine. 2020; 11 (5):a038786.

Chicago/Turabian Style

Jonathan W. Yewdell; Jefferson Santos. 2020. "Original Antigenic Sin: How Original? How Sinful?" Cold Spring Harbor Perspectives in Medicine 11, no. 5: a038786.

Journal article
Published: 01 January 2020 in Journal of Wildlife Diseases
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During 2014, highly pathogenic (HP) influenza A viruses (IAVs) of the A/Goose/Guangdong/1/1996 lineage (GsGD-HP-H5), originating from Asia, were detected in domestic poultry and wild birds in Canada and the US. These clade 2.3.4.4 GsGD-HP-H5 viruses included reassortants possessing North American lineage gene segments; were detected in wild birds in the Pacific, Central, and Mississippi flyways; and caused the largest HP IAV outbreak in poultry in US history. To determine if an antibody response indicative of previous infection with clade 2.3.4.4 GsGD-HP-H5 IAV could be detected in North American wild waterfowl sampled before, during, and after the 2014–15 outbreak, sera from 2,793 geese and 3,715 ducks were tested by blocking enzyme-linked immunosorbent assay and hemagglutination inhibition (HI) tests using both clade 2.3.4.4 GsGD-HP-H5 and North American lineage low pathogenic (LP) H5 IAV antigens. We detected an antibody response meeting a comparative titer-based criteria (HI titer observed with 2.3.4.4 GsGD-HP-H5 antigens exceeded the titer observed for LP H5 antigen by two or more dilutions) for previous infection with clade 2.3.4.4 GsGD-HP-H5 IAV in only five birds, one Blue-winged Teal (Spatula discors) sampled during the outbreak and three Mallards (Anas platyrhynchos) and one Canada Goose (Branta canadensis) sampled during the post-outbreak period. These serologic results are consistent with the spatiotemporal extent of the outbreak in wild birds in North America during 2014 and 2015 and limited exposure of waterfowl to GsGD-HP-H5 IAV, particularly in the central and eastern US.

ACS Style

David E. Stallknecht; Clara Kienzle-Dean; Nick Davis-Fields; Christopher Jennelle; Andrew S. Bowman; Jacqueline M. Nolting; Walter M. Boyce; James M. Crum; Jefferson Santos; Justin D. Brown; Diann J. Prosser; Susan E. W. De La Cruz; Joshua T. Ackerman; Michael L. Casazza; Scott Krauss; Daniel Perez; Andrew M. Ramey; Rebecca L. Poulson. LIMITED DETECTION OF ANTIBODIES TO CLADE 2.3.4.4 A/GOOSE/GUANGDONG/1/1996 LINEAGE HIGHLY PATHOGENIC H5 AVIAN INFLUENZA VIRUS IN NORTH AMERICAN WATERFOWL. Journal of Wildlife Diseases 2020, 56, 47 .

AMA Style

David E. Stallknecht, Clara Kienzle-Dean, Nick Davis-Fields, Christopher Jennelle, Andrew S. Bowman, Jacqueline M. Nolting, Walter M. Boyce, James M. Crum, Jefferson Santos, Justin D. Brown, Diann J. Prosser, Susan E. W. De La Cruz, Joshua T. Ackerman, Michael L. Casazza, Scott Krauss, Daniel Perez, Andrew M. Ramey, Rebecca L. Poulson. LIMITED DETECTION OF ANTIBODIES TO CLADE 2.3.4.4 A/GOOSE/GUANGDONG/1/1996 LINEAGE HIGHLY PATHOGENIC H5 AVIAN INFLUENZA VIRUS IN NORTH AMERICAN WATERFOWL. Journal of Wildlife Diseases. 2020; 56 (1):47.

Chicago/Turabian Style

David E. Stallknecht; Clara Kienzle-Dean; Nick Davis-Fields; Christopher Jennelle; Andrew S. Bowman; Jacqueline M. Nolting; Walter M. Boyce; James M. Crum; Jefferson Santos; Justin D. Brown; Diann J. Prosser; Susan E. W. De La Cruz; Joshua T. Ackerman; Michael L. Casazza; Scott Krauss; Daniel Perez; Andrew M. Ramey; Rebecca L. Poulson. 2020. "LIMITED DETECTION OF ANTIBODIES TO CLADE 2.3.4.4 A/GOOSE/GUANGDONG/1/1996 LINEAGE HIGHLY PATHOGENIC H5 AVIAN INFLUENZA VIRUS IN NORTH AMERICAN WATERFOWL." Journal of Wildlife Diseases 56, no. 1: 47.

Research article
Published: 18 June 2019 in Proceedings of the National Academy of Sciences
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A major obstacle to vaccination against antigenically variable viruses is skewing of antibody responses to variable immunodominant epitopes. For influenza virus hemagglutinin (HA), the immunodominance of the variable head impairs responses to the highly conserved stem. Here, we show that head immunodominance depends on the physical attachment of head to stem. Stem immunogenicity is enhanced by immunizing with stem-only constructs or by increasing local HA concentration in the draining lymph node. Surprisingly, coimmunization of full-length HA and stem alters stem-antibody class switching. Our findings delineate strategies for overcoming immunodominance, with important implications for human vaccination.

ACS Style

Davide Angeletti; Ivan Kosik; Jefferson J. S. Santos; William T. Yewdell; Carolyn M. Boudreau; Vamsee V. A. Mallajosyula; Madeleine C. Mankowski; Michael Chambers; Madhu Prabhakaran; Heather D. Hickman; Adrian B. McDermott; Galit Alter; Jayanta Chaudhuri; Jonathan W. Yewdell. Outflanking immunodominance to target subdominant broadly neutralizing epitopes. Proceedings of the National Academy of Sciences 2019, 116, 13474 -13479.

AMA Style

Davide Angeletti, Ivan Kosik, Jefferson J. S. Santos, William T. Yewdell, Carolyn M. Boudreau, Vamsee V. A. Mallajosyula, Madeleine C. Mankowski, Michael Chambers, Madhu Prabhakaran, Heather D. Hickman, Adrian B. McDermott, Galit Alter, Jayanta Chaudhuri, Jonathan W. Yewdell. Outflanking immunodominance to target subdominant broadly neutralizing epitopes. Proceedings of the National Academy of Sciences. 2019; 116 (27):13474-13479.

Chicago/Turabian Style

Davide Angeletti; Ivan Kosik; Jefferson J. S. Santos; William T. Yewdell; Carolyn M. Boudreau; Vamsee V. A. Mallajosyula; Madeleine C. Mankowski; Michael Chambers; Madhu Prabhakaran; Heather D. Hickman; Adrian B. McDermott; Galit Alter; Jayanta Chaudhuri; Jonathan W. Yewdell. 2019. "Outflanking immunodominance to target subdominant broadly neutralizing epitopes." Proceedings of the National Academy of Sciences 116, no. 27: 13474-13479.

Journal article
Published: 15 March 2019 in Journal of Virology
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A single amino acid change at position 226 in the hemagglutinin (HA) from glutamine (Q) to leucine (L) has been shown to play a key role in receptor specificity switching in various influenza virus HA subtypes, including H9. We tested the flexibility of amino acid usage and determined the effects of such changes. The results reveal that amino acids other than L226 and Q226 are well tolerated and that some amino acids allow for the recognition of both avian and human influenza virus receptors in the absence of other changes. Our results can inform better avian influenza virus surveillance efforts as well as contribute to rational vaccine design and improve structural molecular dynamics algorithms.

ACS Style

Adebimpe Obadan; Jefferson Santos; Lucas Ferreri; Andrew J. Thompson; Silvia Carnaccini; Ginger Geiger; Ana S. Gonzalez Reiche; Daniela S. Rajão; James C. Paulson; Daniel R. Perez. Flexibility In Vitro of Amino Acid 226 in the Receptor-Binding Site of an H9 Subtype Influenza A Virus and Its Effect In Vivo on Virus Replication, Tropism, and Transmission. Journal of Virology 2019, 93, 1 .

AMA Style

Adebimpe Obadan, Jefferson Santos, Lucas Ferreri, Andrew J. Thompson, Silvia Carnaccini, Ginger Geiger, Ana S. Gonzalez Reiche, Daniela S. Rajão, James C. Paulson, Daniel R. Perez. Flexibility In Vitro of Amino Acid 226 in the Receptor-Binding Site of an H9 Subtype Influenza A Virus and Its Effect In Vivo on Virus Replication, Tropism, and Transmission. Journal of Virology. 2019; 93 (6):1.

Chicago/Turabian Style

Adebimpe Obadan; Jefferson Santos; Lucas Ferreri; Andrew J. Thompson; Silvia Carnaccini; Ginger Geiger; Ana S. Gonzalez Reiche; Daniela S. Rajão; James C. Paulson; Daniel R. Perez. 2019. "Flexibility In Vitro of Amino Acid 226 in the Receptor-Binding Site of an H9 Subtype Influenza A Virus and Its Effect In Vivo on Virus Replication, Tropism, and Transmission." Journal of Virology 93, no. 6: 1.

Journal article
Published: 12 March 2019 in Veterinary Microbiology
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Highly pathogenic avian influenza (HPAI) is a viral disease with devastating consequences to the poultry industry as it results in high morbidity, mortality and international trade restrictions. In the present study, we characterized age-related differences in terms of pathology in commercial white broad breasted turkeys inoculated with A/turkey/Minnesota/12582/2015 (H5N2) HPAIV clade 2.3.4.4A, a virus from the largest HPAI poultry outbreak that affected the Unites States in 2014–2015. Turkeys infected at 6-weeks of age showed inapparent to little clinical signs with rapid disease progression, reaching 100% mortality at 3 days post infection (dpi). In contrast, turkeys infected at 16-weeks of age developed ataxia and lethargy and reached 100% mortality by 5 dpi. Infection in the 6-weeks old turkeys resulted in peracute lesions consistent of extensive hemorrhages, edema and necrosis, but inflammation was not prominent. In the 16-weeks old turkeys, necrosis and hemorrhages in tissues were accompanied by a more prominent subacute inflammatory infiltrate. Both age groups showed presence of avian influenza virus (AIV) nucleoprotein (NP) in multiple cell types including neurons, glial cells, ependymal cells, respiratory epithelial cells, air capillary epithelium and pulmonary macrophages, cardiac myocytes, smooth muscle fibers, pancreatic acini and ductal cells. Cells of the vascular walls stained strongly positive for viral antigens, but no positivity was found in the endothelial cells of any organs. These findings indicate that age is a determinant factor in the progression of the disease and delay of mortality during infection with the H5N2 clade 2.3.4.4A HPAI virus in naïve white broad breasted turkeys.

ACS Style

S. Carnaccini; Jefferson Santos; A.O. Obadan; M.J. Pantin-Jackwood; David Suarez; D.S. Rajão; D.R. Perez. Age-dependent pathogenesis of clade 2.3.4.4A H5N2 HPAIV in experimentally infected Broad Breasted White turkeys. Veterinary Microbiology 2019, 231, 183 -190.

AMA Style

S. Carnaccini, Jefferson Santos, A.O. Obadan, M.J. Pantin-Jackwood, David Suarez, D.S. Rajão, D.R. Perez. Age-dependent pathogenesis of clade 2.3.4.4A H5N2 HPAIV in experimentally infected Broad Breasted White turkeys. Veterinary Microbiology. 2019; 231 ():183-190.

Chicago/Turabian Style

S. Carnaccini; Jefferson Santos; A.O. Obadan; M.J. Pantin-Jackwood; David Suarez; D.S. Rajão; D.R. Perez. 2019. "Age-dependent pathogenesis of clade 2.3.4.4A H5N2 HPAIV in experimentally infected Broad Breasted White turkeys." Veterinary Microbiology 231, no. : 183-190.

Journal article
Published: 15 January 2019 in Virology
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Current influenza vaccines including live attenuated influenza virus (LAIV) provide suboptimal protection against drift and potential pandemic strains. We hypothesized that supplementing LAIV with a highly conserved antigenic target M2 ectodomain (M2e) would confer cross-protection by inducing humoral and cellular immune responses to conserved antigenic targets. Intranasal vaccination with LAIV (A/Netherlands/602/09, H1N1) supplemented with tandem repeat M2e containing virus-like particles (M2e5x VLP) induced M2e- and virus-specific antibodies. Upon heterosubtypic virus challenge, M2e5x VLP-supplemented LAIV vaccination of mice induced significantly improved cross protection by preventing weight loss and lowering lung viral titers. Further mechanistic studies on heterosubtypic immunity suggest that T cell responses to M2e and nucleoprotein as well as systemic and mucosal antibodies to M2e and viruses might be contributing to cross protection. Therefore, this study demonstrates a novel vaccination strategy to improve the cross protective efficacy of LAIV by supplementing with a conserved M2e antigenic target.

ACS Style

Young-Tae Lee; Ki-Hye Kim; Eun-Ju Ko; Min-Chul Kim; Yu-Na Lee; Hye-Suk Hwang; Youri Lee; Yu-Jin Jung; Yu Jin Kim; Jefferson Santos; Daniel R. Perez; Sang-Moo Kang. Enhancing the cross protective efficacy of live attenuated influenza virus vaccine by supplemented vaccination with M2 ectodomain virus-like particles. Virology 2019, 529, 111 -121.

AMA Style

Young-Tae Lee, Ki-Hye Kim, Eun-Ju Ko, Min-Chul Kim, Yu-Na Lee, Hye-Suk Hwang, Youri Lee, Yu-Jin Jung, Yu Jin Kim, Jefferson Santos, Daniel R. Perez, Sang-Moo Kang. Enhancing the cross protective efficacy of live attenuated influenza virus vaccine by supplemented vaccination with M2 ectodomain virus-like particles. Virology. 2019; 529 ():111-121.

Chicago/Turabian Style

Young-Tae Lee; Ki-Hye Kim; Eun-Ju Ko; Min-Chul Kim; Yu-Na Lee; Hye-Suk Hwang; Youri Lee; Yu-Jin Jung; Yu Jin Kim; Jefferson Santos; Daniel R. Perez; Sang-Moo Kang. 2019. "Enhancing the cross protective efficacy of live attenuated influenza virus vaccine by supplemented vaccination with M2 ectodomain virus-like particles." Virology 529, no. : 111-121.

Journal article
Published: 15 January 2019 in Journal of Virology
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The complex and continuous antigenic evolution of IAVs remains a major hurdle for vaccine selection and effective vaccination. On the hemagglutinin (HA) of the H3N2 IAVs, the amino acid substitution N 145 K causes significant antigenic changes. We show that amino acid 145 displays remarkable amino acid plasticity in vitro , tolerating multiple amino acid substitutions, many of which have not yet been observed in nature. Mutant viruses carrying substitutions at residue 145 showed no major impairment in virus replication in the presence of lower receptor binding avidity. However, their antigenic characterization confirmed the impact of the 145 K substitution in antibody immunodominance. We provide a better understanding of the functional effects of amino acid substitutions implicated in antigenic drift and its consequences for receptor binding and antigenicity. The mutation analyses presented in this report represent a significant data set to aid and test the ability of computational approaches to predict binding of glycans and in antigenic cartography analyses.

ACS Style

Jefferson J. S. Santos; Eugenio J. Abente; Adebimpe O. Obadan; Andrew J. Thompson; Lucas Ferreri; Ginger Geiger; Ana S. Gonzalez-Reiche; Nicola S. Lewis; David F. Burke; Daniela S. Rajão; James C. Paulson; Amy L. Vincent; Daniel R. Perez. Plasticity of Amino Acid Residue 145 Near the Receptor Binding Site of H3 Swine Influenza A Viruses and Its Impact on Receptor Binding and Antibody Recognition. Journal of Virology 2019, 93, 1 .

AMA Style

Jefferson J. S. Santos, Eugenio J. Abente, Adebimpe O. Obadan, Andrew J. Thompson, Lucas Ferreri, Ginger Geiger, Ana S. Gonzalez-Reiche, Nicola S. Lewis, David F. Burke, Daniela S. Rajão, James C. Paulson, Amy L. Vincent, Daniel R. Perez. Plasticity of Amino Acid Residue 145 Near the Receptor Binding Site of H3 Swine Influenza A Viruses and Its Impact on Receptor Binding and Antibody Recognition. Journal of Virology. 2019; 93 (2):1.

Chicago/Turabian Style

Jefferson J. S. Santos; Eugenio J. Abente; Adebimpe O. Obadan; Andrew J. Thompson; Lucas Ferreri; Ginger Geiger; Ana S. Gonzalez-Reiche; Nicola S. Lewis; David F. Burke; Daniela S. Rajão; James C. Paulson; Amy L. Vincent; Daniel R. Perez. 2019. "Plasticity of Amino Acid Residue 145 Near the Receptor Binding Site of H3 Swine Influenza A Viruses and Its Impact on Receptor Binding and Antibody Recognition." Journal of Virology 93, no. 2: 1.

Book chapter
Published: 01 January 2019 in Avian Virology: Current Research and Future Trends
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Covers all the important avian viruses over thirteen chapters. Examples include: avian influenza virus, avian adenovirus, Marek's disease virus, avian reovirus, avian pox virus, avian leukosis virus, avian metapneumovirus, avian paramyxovirus. Closes with a chapter on the avian immune responses to virus infection.

ACS Style

Daniel R. Perez; Silvia Carnaccini; Stivalis Cardenas Garcia; Lucas Ferreri; Jefferson Santos; Daniela S. Rajao. Avian Influenza Virus. Avian Virology: Current Research and Future Trends 2019, 1 .

AMA Style

Daniel R. Perez, Silvia Carnaccini, Stivalis Cardenas Garcia, Lucas Ferreri, Jefferson Santos, Daniela S. Rajao. Avian Influenza Virus. Avian Virology: Current Research and Future Trends. 2019; ():1.

Chicago/Turabian Style

Daniel R. Perez; Silvia Carnaccini; Stivalis Cardenas Garcia; Lucas Ferreri; Jefferson Santos; Daniela S. Rajao. 2019. "Avian Influenza Virus." Avian Virology: Current Research and Future Trends , no. : 1.

Comparative study
Published: 15 November 2018 in Journal of Virology
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Due to the rapid evolution of the influenza A virus, vaccines require continuous strain updates. Additionally, the platform used to deliver the vaccine can have an impact on the breadth of protection. Currently, there are various vaccine platforms available to prevent influenza A virus infection in swine, and we experimentally tested two: adjuvanted-whole inactivated virus and live-attenuated virus. When challenged with an antigenically distinct virus, adjuvanted-whole inactivated virus provided partial protection, while live-attenuated virus provided effective protection. Additional strategies are required to broaden the protective properties of inactivated virus vaccines, given the dynamic antigenic landscape of cocirculating strains in North America, whereas live-attenuated vaccines may require less frequent strain updates, based on demonstrated cross-protection. Enhancing vaccine efficacy to control influenza infections in swine will help reduce the impact they have on swine production and reduce the risk of swine-to-human transmission.

ACS Style

Eugenio J. Abente; Daniela S. Rajao; Jefferson Santos; Bryan S. Kaplan; Tracy L. Nicholson; Susan L. Brockmeier; Phillip C. Gauger; Daniel R. Perez; Amy L. Vincent. Comparison of Adjuvanted-Whole Inactivated Virus and Live-Attenuated Virus Vaccines against Challenge with Contemporary, Antigenically Distinct H3N2 Influenza A Viruses. Journal of Virology 2018, 92, e01323-18 .

AMA Style

Eugenio J. Abente, Daniela S. Rajao, Jefferson Santos, Bryan S. Kaplan, Tracy L. Nicholson, Susan L. Brockmeier, Phillip C. Gauger, Daniel R. Perez, Amy L. Vincent. Comparison of Adjuvanted-Whole Inactivated Virus and Live-Attenuated Virus Vaccines against Challenge with Contemporary, Antigenically Distinct H3N2 Influenza A Viruses. Journal of Virology. 2018; 92 (22):e01323-18.

Chicago/Turabian Style

Eugenio J. Abente; Daniela S. Rajao; Jefferson Santos; Bryan S. Kaplan; Tracy L. Nicholson; Susan L. Brockmeier; Phillip C. Gauger; Daniel R. Perez; Amy L. Vincent. 2018. "Comparison of Adjuvanted-Whole Inactivated Virus and Live-Attenuated Virus Vaccines against Challenge with Contemporary, Antigenically Distinct H3N2 Influenza A Viruses." Journal of Virology 92, no. 22: e01323-18.

Journal article
Published: 01 November 2018 in Journal of Virology
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Seasonal influenza viruses infect 1 billion people worldwide and are associated with ∼500,000 deaths annually. In addition, the never-ending emergence of zoonotic influenza viruses associated with lethal human infections and of pandemic concern calls for the development of better vaccines and/or vaccination strategies against influenza virus. Regardless of the strategy, novel influenza virus vaccines must aim at providing protection against both seasonal influenza A and B viruses. In this study, we tested an alternative quadrivalent live attenuated influenza virus vaccine (QIV) formulation whose individual components have been previously shown to provide protection. We demonstrate in proof-of principle studies in mice that the QIV provides effective protection against lethal challenge with either influenza A or B virus.

ACS Style

Zhimin Wan; Stivalis Cardenas Garcia; Jing Liu; Jefferson Santos; Silvia Carnaccini; Ginger Geiger; Lucas Ferreri; Daniela Rajao; Daniel R. Perez. Alternative Strategy for a Quadrivalent Live Attenuated Influenza Virus Vaccine. Journal of Virology 2018, 92, e01025-18 .

AMA Style

Zhimin Wan, Stivalis Cardenas Garcia, Jing Liu, Jefferson Santos, Silvia Carnaccini, Ginger Geiger, Lucas Ferreri, Daniela Rajao, Daniel R. Perez. Alternative Strategy for a Quadrivalent Live Attenuated Influenza Virus Vaccine. Journal of Virology. 2018; 92 (21):e01025-18.

Chicago/Turabian Style

Zhimin Wan; Stivalis Cardenas Garcia; Jing Liu; Jefferson Santos; Silvia Carnaccini; Ginger Geiger; Lucas Ferreri; Daniela Rajao; Daniel R. Perez. 2018. "Alternative Strategy for a Quadrivalent Live Attenuated Influenza Virus Vaccine." Journal of Virology 92, no. 21: e01025-18.

Short communication
Published: 01 February 2018 in Revista da Sociedade Brasileira de Medicina Tropical
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Keywords: Yellow fever virus; Trans-packaging; Pseudo-infectious particles

ACS Style

Sabrina Ribeiro De Almeida Queiroz; José Valter Joaquim Silva Júnior; Andréa Nazaré Monteiro Rangel Da Silva; Amanda Gomes De Oliveira Carvalho; Jefferson Jose Da Silva Santos; Laura Helena Vega Gonzales Gil. Development and characterization of a packaging cell line for pseudo-infectious yellow fever virus particle generation. Revista da Sociedade Brasileira de Medicina Tropical 2018, 51, 66 -70.

AMA Style

Sabrina Ribeiro De Almeida Queiroz, José Valter Joaquim Silva Júnior, Andréa Nazaré Monteiro Rangel Da Silva, Amanda Gomes De Oliveira Carvalho, Jefferson Jose Da Silva Santos, Laura Helena Vega Gonzales Gil. Development and characterization of a packaging cell line for pseudo-infectious yellow fever virus particle generation. Revista da Sociedade Brasileira de Medicina Tropical. 2018; 51 (1):66-70.

Chicago/Turabian Style

Sabrina Ribeiro De Almeida Queiroz; José Valter Joaquim Silva Júnior; Andréa Nazaré Monteiro Rangel Da Silva; Amanda Gomes De Oliveira Carvalho; Jefferson Jose Da Silva Santos; Laura Helena Vega Gonzales Gil. 2018. "Development and characterization of a packaging cell line for pseudo-infectious yellow fever virus particle generation." Revista da Sociedade Brasileira de Medicina Tropical 51, no. 1: 66-70.

Book chapter
Published: 26 December 2017 in Tropical Diseases: An Overview of Major Diseases Occurring in the Americas
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ACS Style

Andrea N. M. R. Da Silva; Jefferson J. S. Santos; Laura H.V.G. Gil. Dengue Fever: New Tools for Treatment and Prevention. Tropical Diseases: An Overview of Major Diseases Occurring in the Americas 2017, 286 -308.

AMA Style

Andrea N. M. R. Da Silva, Jefferson J. S. Santos, Laura H.V.G. Gil. Dengue Fever: New Tools for Treatment and Prevention. Tropical Diseases: An Overview of Major Diseases Occurring in the Americas. 2017; ():286-308.

Chicago/Turabian Style

Andrea N. M. R. Da Silva; Jefferson J. S. Santos; Laura H.V.G. Gil. 2017. "Dengue Fever: New Tools for Treatment and Prevention." Tropical Diseases: An Overview of Major Diseases Occurring in the Americas , no. : 286-308.

Journal article
Published: 06 September 2017 in Vaccine
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Highly pathogenic avian influenza virus (HPAIV) infections are frequently associated with systemic disease and high mortality in domestic poultry, particularly in chickens and turkeys. Clade 2.3.4.4 represents a genetic cluster within the Asian HPAIV H5 Goose/Guangdong lineage that has transmitted through migratory birds and spread throughout the world. In 2014, clade 2.3.4.4 strains entered the U.S. via the Pacific flyway, reassorted with local strains of the North American lineage, and produced novel HPAIV strains of the H5N1, H5N2, and H5N8 subtypes. By 2015, the H5N2 HPAIVs disseminated eastwards within the continental U.S. and Canada and infected commercial poultry, causing the largest animal health outbreak in recent history in the U.S. The outbreak was controlled by traditional mass depopulation methods, but the outbreak was of such magnitude that it led to the consideration of alternative control measures, including vaccination. In this regard, little information is available on the long-term protection of turkeys vaccinated against avian influenza. In this report, a vaccination study was carried out in turkeys using 3 prime-boost approaches with a combination of 2 different vaccines, an alphavirus-based replicon vaccine and an adjuvanted-inactivated reverse genetics vaccine. Vaccine efficacy was assessed at 6 and 16 weeks of age following challenge with a prototypic novel clade 2.3.4.4 H5N2 HPAIV. All three vaccines protocols were protective with significantly reduced virus shedding and mortality after challenge at 6 weeks of age. In contrast, significant variations were seen in 16-week old turkeys after challenge: priming with the alphavirus-based replicon followed by boost with the adjuvanted-inactivated vaccine conferred the best protection, whereas the alphavirus-based replicon vaccine given twice provided the least protection. Our study highlights the importance of studying not only different vaccine platforms but also vaccination strategies to maximize protection against HPAIV especially with regards to the longevity of vaccine-induced immune response.

ACS Style

Jefferson Santos; Adebimpe Obadan; Stivalis Cardenas Garcia; Silvia Carnaccini; Darrell R. Kapczynski; Mary J. Pantin-Jackwood; David Suarez; Daniel R. Perez. Short- and long-term protective efficacy against clade 2.3.4.4 H5N2 highly pathogenic avian influenza virus following prime-boost vaccination in turkeys. Vaccine 2017, 35, 5637 -5643.

AMA Style

Jefferson Santos, Adebimpe Obadan, Stivalis Cardenas Garcia, Silvia Carnaccini, Darrell R. Kapczynski, Mary J. Pantin-Jackwood, David Suarez, Daniel R. Perez. Short- and long-term protective efficacy against clade 2.3.4.4 H5N2 highly pathogenic avian influenza virus following prime-boost vaccination in turkeys. Vaccine. 2017; 35 (42):5637-5643.

Chicago/Turabian Style

Jefferson Santos; Adebimpe Obadan; Stivalis Cardenas Garcia; Silvia Carnaccini; Darrell R. Kapczynski; Mary J. Pantin-Jackwood; David Suarez; Daniel R. Perez. 2017. "Short- and long-term protective efficacy against clade 2.3.4.4 H5N2 highly pathogenic avian influenza virus following prime-boost vaccination in turkeys." Vaccine 35, no. 42: 5637-5643.

Journal article
Published: 15 June 2017 in Journal of Virology
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Influenza B virus (IBV) is considered a major human pathogen, responsible for seasonal epidemics of acute respiratory illness. Two antigenically distinct IBV hemagglutinin (HA) lineages cocirculate worldwide with little cross-reactivity. Live attenuated influenza virus (LAIV) vaccines have been shown to provide better cross-protective immune responses than inactivated vaccines by eliciting local mucosal immunity and systemic B cell- and T cell-mediated memory responses. We have shown previously that incorporation of temperature-sensitive ( ts ) mutations into the PB1 and PB2 subunits along with a modified HA epitope tag in the C terminus of PB1 resulted in influenza A viruses (IAV) that are safe and effective as modified live attenuated ( att ) virus vaccines (IAV att ). We explored whether analogous mutations in the IBV polymerase subunits would result in a stable virus with an att phenotype. The PB1 subunit of the influenza B/Brisbane/60/2008 strain was used to incorporate ts mutations and a C-terminal HA tag. Such modifications resulted in a B/Bris att strain with ts characteristics in vitro and an att phenotype in vivo . Vaccination studies in mice showed that a single dose of the B/Bris att candidate stimulated sterilizing immunity against lethal homologous challenge and complete protection against heterologous challenge. These studies show the potential of an alternative LAIV platform for the development of IBV vaccines. IMPORTANCE A number of issues with regard to the effectiveness of the LAIV vaccine licensed in the United States (FluMist) have arisen over the past three seasons (2013–2014, 2014–2015, and 2015–2016). While the reasons for the limited robustness of the vaccine-elicited immune response remain controversial, this problem highlights the critical importance of continued investment in LAIV development and creates an opportunity to improve current strategies so as to develop more efficacious vaccines. Our laboratory has developed an alternative strategy, the incorporation of 2 amino acid mutations and a modified HA tag at the C terminus of PB1, which is sufficient to attenuate the IBV. As a LAIV, this novel vaccine provides complete protection against IBV strains. The availability of attenuated IAV and IBV backbones based on contemporary strains offers alternative platforms for the development of LAIVs that may overcome current limitations.

ACS Style

Jefferson J. S. Santos; Courtney Finch; Troy Sutton; Adebimpe Obadan; Isabel Aguirre; Zhimin Wan; Diego Lopez; Ginger Geiger; Ana Silvia Gonzalez-Reiche; Lucas Ferreri; Daniel R. Perez. Development of an Alternative Modified Live Influenza B Virus Vaccine. Journal of Virology 2017, 91, e00056-17 .

AMA Style

Jefferson J. S. Santos, Courtney Finch, Troy Sutton, Adebimpe Obadan, Isabel Aguirre, Zhimin Wan, Diego Lopez, Ginger Geiger, Ana Silvia Gonzalez-Reiche, Lucas Ferreri, Daniel R. Perez. Development of an Alternative Modified Live Influenza B Virus Vaccine. Journal of Virology. 2017; 91 (12):e00056-17.

Chicago/Turabian Style

Jefferson J. S. Santos; Courtney Finch; Troy Sutton; Adebimpe Obadan; Isabel Aguirre; Zhimin Wan; Diego Lopez; Ginger Geiger; Ana Silvia Gonzalez-Reiche; Lucas Ferreri; Daniel R. Perez. 2017. "Development of an Alternative Modified Live Influenza B Virus Vaccine." Journal of Virology 91, no. 12: e00056-17.

Protocol
Published: 16 May 2017 in Methods in Molecular Biology
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Influenza A viruses have broad host range with a recognized natural reservoir in wild aquatic birds. From this reservoir, novel strains occasionally emerge with the potential to establish stable lineages in other avian and mammalian species, including humans. Understanding the molecular changes that allow influenza A viruses to change host range is essential to better assess their animal and public health risks. Reverse genetics systems have transformed the ability to manipulate and study negative strand RNA viruses. In the particular case of influenza A viruses, plasmid-based reverse genetics approaches have allowed for a better understanding of, among others, virulence, transmission, mechanisms of antiviral resistance, and the development of alternative vaccines and vaccination strategies. In this chapter we describe the cloning of cDNA copies of viral RNA segments derived from a type A influenza virus into reverse genetics plasmid vectors and the experimental procedures for the successful generation of recombinant influenza A viruses.

ACS Style

Daniel R. Perez; Matthew Angel; Ana Silvia Gonzalez-Reiche; Jefferson Santos; Adebimpe Obadan; Luis Martinez-Sobrido. Plasmid-Based Reverse Genetics of Influenza A Virus. Methods in Molecular Biology 2017, 1602, 251 -273.

AMA Style

Daniel R. Perez, Matthew Angel, Ana Silvia Gonzalez-Reiche, Jefferson Santos, Adebimpe Obadan, Luis Martinez-Sobrido. Plasmid-Based Reverse Genetics of Influenza A Virus. Methods in Molecular Biology. 2017; 1602 ():251-273.

Chicago/Turabian Style

Daniel R. Perez; Matthew Angel; Ana Silvia Gonzalez-Reiche; Jefferson Santos; Adebimpe Obadan; Luis Martinez-Sobrido. 2017. "Plasmid-Based Reverse Genetics of Influenza A Virus." Methods in Molecular Biology 1602, no. : 251-273.

Protocol
Published: 16 May 2017 in Methods in Molecular Biology
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Annual influenza epidemics are caused not only by influenza A viruses but also by influenza B viruses. Initially established for the generation of recombinant influenza A viruses, plasmid-based reverse genetics techniques have allowed researchers the generation of wild type and mutant viruses from full-length cDNA copies of the influenza viral genome. These reverse genetics approaches have allowed researchers to answer important questions on the biology of influenza viruses by genetically engineering infectious recombinant viruses. This has resulted in a better understanding of the molecular biology of influenza viruses, including both viral and host factors required for genome replication and transcription. With the ability to generate recombinant viruses containing specific mutations in the viral genome, these reverse genetics tools have also allowed the identification of viral and host factors involved in influenza pathogenesis, transmissibility, host-range interactions and restrictions, and virulence. Likewise, reverse genetics techniques have been used for the implementation of inactivated or live-attenuated influenza vaccines and the identification of anti-influenza drugs and their mechanism of antiviral activity. In 2002, these reverse genetics approaches allowed also the recovery of recombinant influenza B viruses entirely from plasmid DNA. In this chapter we describe the cloning of influenza B/Brisbane/60/2008 viral RNAs into the ambisense pDP-2002 plasmid and the experimental procedures for the successful generation of recombinant influenza B viruses.

ACS Style

Aitor Nogales; Daniel R. Perez; Jefferson Santos; Courtney Finch; Luis Martínez-Sobrido. Reverse Genetics of Influenza B Viruses. Methods in Molecular Biology 2017, 1602, 205 -238.

AMA Style

Aitor Nogales, Daniel R. Perez, Jefferson Santos, Courtney Finch, Luis Martínez-Sobrido. Reverse Genetics of Influenza B Viruses. Methods in Molecular Biology. 2017; 1602 ():205-238.

Chicago/Turabian Style

Aitor Nogales; Daniel R. Perez; Jefferson Santos; Courtney Finch; Luis Martínez-Sobrido. 2017. "Reverse Genetics of Influenza B Viruses." Methods in Molecular Biology 1602, no. : 205-238.

Journal article
Published: 06 January 2017 in The Journal of Immunology
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Human infections with highly pathogenic avian influenza A (H5N1) virus are frequently fatal but the mechanisms of disease remain ill-defined. H5N1 infection is associated with intense production of proinflammatory cytokines, but whether this cytokine storm is the main cause of fatality or is a consequence of extensive virus replication that itself drives disease remains controversial. Conventional intratracheal inoculation of a liquid suspension of H5N1 influenza virus in nonhuman primates likely results in efficient clearance of virus within the upper respiratory tract and rarely produces severe disease. We reasoned that small particle aerosols of virus would penetrate the lower respiratory tract and blanket alveoli where target cells reside. We show that inhalation of aerosolized H5N1 influenza virus in cynomolgus macaques results in fulminant pneumonia that rapidly progresses to acute respiratory distress syndrome with a fatal outcome reminiscent of human disease. Molecular imaging revealed intense lung inflammation coincident with massive increases in proinflammatory proteins and IFN-α in distal airways. Aerosolized H5N1 exposure decimated alveolar macrophages, which were widely infected and caused marked influx of interstitial macrophages and neutrophils. Extensive infection of alveolar epithelial cells caused apoptosis and leakage of albumin into airways, reflecting loss of epithelial barrier function. These data establish inhalation of aerosolized virus as a critical source of exposure for fatal human infection and reveal that direct viral effects in alveoli mediate H5N1 disease. This new nonhuman primate model will advance vaccine and therapeutic approaches to prevent and treat human disease caused by highly pathogenic avian influenza viruses.

ACS Style

Elizabeth R. Wonderlich; Zachary D. Swan; Stephanie J. Bissel; Amy L. Hartman; Jonathan P. Carney; Katherine J. O’Malley; Adebimpe O. Obadan; Jefferson Santos; Reagan Walker; Timothy J. Sturgeon; Lonnie J. Frye; Pauline Maiello; Charles A. Scanga; Jennifer D. Bowling; Anthea L. Bouwer; Parichat A. Duangkhae; Clayton A. Wiley; JoAnne L. Flynn; Jieru Wang; Kelly S. Cole; Daniel R. Perez; Douglas S. Reed; Simon M. Barratt-Boyes. Widespread Virus Replication in Alveoli Drives Acute Respiratory Distress Syndrome in Aerosolized H5N1 Influenza Infection of Macaques. The Journal of Immunology 2017, 198, 1616 -1626.

AMA Style

Elizabeth R. Wonderlich, Zachary D. Swan, Stephanie J. Bissel, Amy L. Hartman, Jonathan P. Carney, Katherine J. O’Malley, Adebimpe O. Obadan, Jefferson Santos, Reagan Walker, Timothy J. Sturgeon, Lonnie J. Frye, Pauline Maiello, Charles A. Scanga, Jennifer D. Bowling, Anthea L. Bouwer, Parichat A. Duangkhae, Clayton A. Wiley, JoAnne L. Flynn, Jieru Wang, Kelly S. Cole, Daniel R. Perez, Douglas S. Reed, Simon M. Barratt-Boyes. Widespread Virus Replication in Alveoli Drives Acute Respiratory Distress Syndrome in Aerosolized H5N1 Influenza Infection of Macaques. The Journal of Immunology. 2017; 198 (4):1616-1626.

Chicago/Turabian Style

Elizabeth R. Wonderlich; Zachary D. Swan; Stephanie J. Bissel; Amy L. Hartman; Jonathan P. Carney; Katherine J. O’Malley; Adebimpe O. Obadan; Jefferson Santos; Reagan Walker; Timothy J. Sturgeon; Lonnie J. Frye; Pauline Maiello; Charles A. Scanga; Jennifer D. Bowling; Anthea L. Bouwer; Parichat A. Duangkhae; Clayton A. Wiley; JoAnne L. Flynn; Jieru Wang; Kelly S. Cole; Daniel R. Perez; Douglas S. Reed; Simon M. Barratt-Boyes. 2017. "Widespread Virus Replication in Alveoli Drives Acute Respiratory Distress Syndrome in Aerosolized H5N1 Influenza Infection of Macaques." The Journal of Immunology 198, no. 4: 1616-1626.

Journal article
Published: 15 September 2016 in Journal of Virology
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Influenza A virus (IAV) of the H3 subtype is an important respiratory pathogen that affects both humans and swine. Vaccination to induce neutralizing antibodies against the surface glycoprotein hemagglutinin (HA) is the primary method used to control disease. However, due to antigenic drift, vaccine strains must be periodically updated. Six of the 7 positions previously identified in human seasonal H3 (positions 145, 155, 156, 158, 159, 189, and 193) were also indicated in swine H3 antigenic evolution. To experimentally test the effect on virus antigenicity of these 7 positions, substitutions were introduced into the HA of an isogenic swine lineage virus. We tested the antigenic effect of these introduced substitutions by using hemagglutination inhibition (HI) data with monovalent swine antisera and antigenic cartography to evaluate the antigenic phenotype of the mutant viruses. Combinations of substitutions within the antigenic motif caused significant changes in antigenicity. One virus mutant that varied at only two positions relative to the wild type had a >4-fold reduction in HI titers compared to homologous antisera. Potential changes in pathogenesis and transmission of the double mutant were evaluated in pigs. Although the double mutant had virus shedding titers and transmissibility comparable to those of the wild type, it caused a significantly lower percentage of lung lesions. Elucidating the antigenic effects of specific amino acid substitutions at these sites in swine H3 IAV has important implications for understanding IAV evolution within pigs as well as for improved vaccine development and control strategies in swine. IMPORTANCE A key component of influenza virus evolution is antigenic drift mediated by the accumulation of amino acid substitutions in the hemagglutinin (HA) protein, resulting in escape from prior immunity generated by natural infection or vaccination. Understanding which amino acid positions of the HA contribute to the ability of the virus to avoid prior immunity is important for understanding antigenic evolution and informs vaccine efficacy predictions based on the genetic sequence data from currently circulating strains. Following our previous work characterizing antigenic phenotypes of contemporary wild-type swine H3 influenza viruses, we experimentally validated that substitutions at 6 amino acid positions in the HA protein have major effects on antigenicity. An improved understanding of the antigenic diversity of swine influenza will facilitate a rational approach for selecting more effective vaccine components to control the circulation of influenza in pigs and reduce the potential for zoonotic viruses to emerge.

ACS Style

Eugenio Abente; Jefferson Santos; Nicola S. Lewis; Phillip C. Gauger; Jered Stratton; Eugene Skepner; Tavis K. Anderson; Daniela S. Rajao; Daniel R. Perez; Amy L. Vincent. The Molecular Determinants of Antibody Recognition and Antigenic Drift in the H3 Hemagglutinin of Swine Influenza A Virus. Journal of Virology 2016, 90, 8266 -8280.

AMA Style

Eugenio Abente, Jefferson Santos, Nicola S. Lewis, Phillip C. Gauger, Jered Stratton, Eugene Skepner, Tavis K. Anderson, Daniela S. Rajao, Daniel R. Perez, Amy L. Vincent. The Molecular Determinants of Antibody Recognition and Antigenic Drift in the H3 Hemagglutinin of Swine Influenza A Virus. Journal of Virology. 2016; 90 (18):8266-8280.

Chicago/Turabian Style

Eugenio Abente; Jefferson Santos; Nicola S. Lewis; Phillip C. Gauger; Jered Stratton; Eugene Skepner; Tavis K. Anderson; Daniela S. Rajao; Daniel R. Perez; Amy L. Vincent. 2016. "The Molecular Determinants of Antibody Recognition and Antigenic Drift in the H3 Hemagglutinin of Swine Influenza A Virus." Journal of Virology 90, no. 18: 8266-8280.

Evaluation study
Published: 01 October 2015 in Clinical and Vaccine Immunology
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In North American swine, there are numerous antigenically distinct H1 influenza A virus (IAV) variants currently circulating, making vaccine development difficult due to the inability to formulate a vaccine that provides broad cross-protection. Experimentally, live-attenuated influenza virus (LAIV) vaccines demonstrate increased cross-protection compared to inactivated vaccines. However, there is no standardized assay to predict cross-protection following LAIV vaccination. Hemagglutination-inhibiting (HI) antibody in serum is the gold standard correlate of protection following IAV vaccination. LAIV vaccination does not induce a robust serum HI antibody titer; however, a local mucosal antibody response is elicited. Thus, a live-animal sample source that could be used to evaluate LAIV immunogenicity and cross-protection is needed. Here, we evaluated the use of oral fluids (OF) and nasal wash (NW) collected after IAV inoculation as a live-animal sample source in an enzyme-linked immunosorbent assay (ELISA) to predict cross-protection in comparison to traditional serology. Both live-virus exposure and LAIV vaccination provided heterologous protection, though protection was greatest against more closely phylogenetically related viruses. IAV-specific IgA was detected in NW and OF samples and was cross-reactive to representative IAV from each H1 cluster. Endpoint titers of cross-reactive IgA in OF from pigs exposed to live virus was associated with heterologous protection. While LAIV vaccination provided significant protection, LAIV immunogenicity was reduced compared to live-virus exposure. These data suggest that OF from pigs inoculated with wild-type IAV, with surface genes that match the LAIV seed strain, could be used in an ELISA to assess cross-protection and the antigenic relatedness of circulating and emerging IAV in swine.

ACS Style

Holly R. Hughes; Amy L. Vincent; Susan L. Brockmeier; Phillip C. Gauger; Lindomar Pena; Jefferson Santos; Douglas R. Braucher; Daniel R. Perez; Crystal L. Loving. Oral Fluids as a Live-Animal Sample Source for Evaluating Cross-Reactivity and Cross-Protection following Intranasal Influenza A Virus Vaccination in Pigs. Clinical and Vaccine Immunology 2015, 22, 1109 -1120.

AMA Style

Holly R. Hughes, Amy L. Vincent, Susan L. Brockmeier, Phillip C. Gauger, Lindomar Pena, Jefferson Santos, Douglas R. Braucher, Daniel R. Perez, Crystal L. Loving. Oral Fluids as a Live-Animal Sample Source for Evaluating Cross-Reactivity and Cross-Protection following Intranasal Influenza A Virus Vaccination in Pigs. Clinical and Vaccine Immunology. 2015; 22 (10):1109-1120.

Chicago/Turabian Style

Holly R. Hughes; Amy L. Vincent; Susan L. Brockmeier; Phillip C. Gauger; Lindomar Pena; Jefferson Santos; Douglas R. Braucher; Daniel R. Perez; Crystal L. Loving. 2015. "Oral Fluids as a Live-Animal Sample Source for Evaluating Cross-Reactivity and Cross-Protection following Intranasal Influenza A Virus Vaccination in Pigs." Clinical and Vaccine Immunology 22, no. 10: 1109-1120.