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  1. Science & Research (Biologics)

Gastrointestinal Viruses: Understanding Diversity and Immune Responses to Inform Vaccine Design

Gabriel I. Parra, PhD

Office of Vaccines Research and Review
Division of Viral Products
Laboratory of Hepatitis

Gabriel.Parra@fda.hhs.gov


Biosketch

Dr. Gabriel Parra graduated from the School of Sciences, Paraguay and received his MSc and PhD in Biology at the School of Sciences, Uruguay. He completed his postdoctoral training at the Laboratory of Infectious Diseases, National Institutes of Health. In 2016, Dr. Parra became Principal Investigator at the Division of Viral Products, Food and Drug Administration. His research focuses on epidemiology, genomics, evolution, and immunity of viruses associated with gastroenteritis.

The full list of ad hoc review and publications can be found at: https://publons.com/researcher/570335/gabriel-i-parra/


General Overview

Despite substantial reduction in morbidity and mortality from acute gastroenteritis in the last three decades, the disease continues to inflict a high global disease burden. Rotavirus and norovirus are the most important causes of acute gastroenteritis in children under 5 years old. There are two licensed rotavirus vaccines, but none available to prevent norovirus disease.

With the successful implementation of the rotavirus vaccines, noroviruses have emerged as the most important cause of viral gastroenteritis in the US and other developed countries. While good hygiene practices can partially help to prevent infection and spread of disease, the consensus is that vaccination is the most effective option against norovirus diseases.  The major obstacles delaying the development of an effective norovirus vaccine are: 1) the diversity of noroviruses; 2) our limited understanding of immunity to noroviruses; 3) the lack of an animal model to study human noroviruses; 5) the lack of a robust cell culture system, which has hampered the use of traditional techniques to develop viral vaccines.

On the other hand, while rotavirus vaccines have been successfully implemented in developed countries, their efficacy is lower in developing countries. One possible reason for this lower efficacy is the higher diversity of rotavirus in those countries, particularly Asia and Africa. A better understanding of the mechanism of viral diversity could provide insights for vaccine implementation and design.

In our lab we use state-of-the-art technologies to overcome some of these obstacles and generate data that will improve our understanding of norovirus and rotavirus disease. Our research program focuses on: 1) high-throughput characterization of the genetic diversity of norovirus and rotavirus strains; 2) determination of common targets in norovirus and rotavirus proteins that can be used to develop cross-protective vaccines; 3) development of new tools to characterize the antigenic diversification of these viruses;4) development new animal models to assess efficacy of immune responses to human norovirus.

We expect this work will provide important information for vaccine design for human gastrointestinal viruses and help FDA to evaluate the efficacy and safety of these vaccines.


Scientific Overview

Despite improvements in sanitation and vaccination programs, acute gastroenteritis continues to inflict a high global disease burden. Rotavirus and norovirus are the two major causes of viral gastroenteritis worldwide. Recent estimates have indicated that these viruses cause up to 600,000 deaths annually, mainly in developing countries.

While two vaccines for rotaviruses have been successfully implemented in different countries, none are yet available to prevent norovirus disease. One of the obstacles that has prevented the development of an effective norovirus vaccine is the virus’s extreme diversity.  Thus, despite the detection of high levels of cross-reactive antibodies, individuals can have multiple norovirus infections.  Although, cross-protection has been reported for rotavirus vaccines, the lower efficacy of these vaccines in developing countries may be in part linked to the extreme diversity of the virus in those countries.

Our laboratory studies of the role of genetic diversification of noroviruses and rotaviruses in immune protection. Among the aims of our work are to:

  1. determine the antigenic relationship among the different norovirus genotypes;
  2. develop new tools to better understand the rules governing the emergence and diversification of pandemic noroviruses;
  3. develop new in vitro and animal models to study mechanisms of cross-protection against human noroviruses;
    determine the mechanisms of genetic diversification of rotaviruses to understand disease and vaccine breakthrough.

We will use this information to better understand the evolution, immunity, and natural histories of the diseases they cause.  We expect this work will help to identify targets for immune protection and improve the design and use of vaccines against these two deadly viruses.

Different approaches utilized by our lab to study gastrointestinal viruses.

Publications

  1. J Infect Dis 2024 Feb 21 [Epub ahead of print]
    Analysis of archival sera from norovirus-infected individuals demonstrates that cross-blocking of emerging viruses is genotype-specific.
    Pilewski KA, Ford-Siltz LA, Tohma K, Kendra JA, Landivar M, Parra GI
  2. mBio 2023 Dec;14(6):e0217723
    Norovirus evolves as one or more distinct clonal populations in immunocompromised hosts.
    Chaimongkol N, Dábilla N, Tohma K, Matsushima Y, Yardley AB, Levenson EA, Johnson JA, Ahorrio C, Oler AJ, Kim DY, Souza M, Sosnovtsev SV, Parra GI, Green KY
  3. J Virol 2023 Feb;97(2):e0171622
    Minimal antigenic evolution after a decade of norovirus GII.4 Sydney_2012 circulation in humans.
    Parra GI, Tohma K, Ford-Siltz LA, Eguino P, Kendra JA, Pilewski KA, Gao Y
  4. Arch Virol 2022 Dec;167(12):2723-7
    Genetic characteristics of archival noroviruses detected from the 1970s to the 1990s.
    Mori K, Nagano M, Yaoita Y, Asakura H, Suzuki A, Isogai M, Fujiwara T, Nagashima M, Suzuki J, Tohma K, Sadamasu K
  5. Front Immunol 2022 Oct 25;13:1040836
    Cross-reactive neutralizing human monoclonal antibodies mapping to variable antigenic sites on the norovirus major capsid protein.
    Ford-Siltz LA, Tohma K, Alvarado GS, Kendra JA, Pilewski KA, Crowe JE Jr, Parra GI
  6. Rev Med Virol 2022 Sep;32(5):e2354
    Global and regional circulation trends of norovirus genotypes and recombinants, 1995-2019: a comprehensive review of sequences from public databases.
    Kendra JA, Tohma K, Parra GI
  7. J Infect Dis 2022 Apr 1;225(7):1205-14
    Genotype-specific neutralization of norovirus is mediated by antibodies against the protruding domain of the major capsid protein.
    Ford-Siltz LA, Wales S, Tohma K, Gao Y, Parra GI
  8. Cell Rep 2022 Apr 12;39(2):110689
    Dynamic immunodominance hierarchy of neutralizing antibody responses to evolving GII.4 noroviruses.
    Tohma K, Ford-Siltz LA, Kendra JA, Parra GI
  9. Emerg Microbes Infect 2021 Dec;10(1):1717-30
    Viral intra-host evolution in immunocompetent children contributes to human norovirus diversification at the global scale.
    Tohma K, Saito M, Pajuelo MJ, Mayta H, Zimic M, Lepore CJ, Ford-Siltz LA, Gilman RH, Parra GI
  10. PLoS Pathog 2021 Jul 13;17(7):e1009744
    Genome-wide analyses of human noroviruses provide insights on evolutionary dynamics and evidence of coexisting viral populations evolving under recombination constraints.
    Tohma K, Lepore CJ, Martinez M, Degiuseppe JI, Khamrin P, Saito M, Mayta H, Nwaba AUA, Ford-Siltz LA, Green KY, Galeano ME, Zimic M, Stupka JA, Gilman RH, Maneekarn N, Ushijima H, Parra GI
  11. Proc Natl Acad Sci U S A 2021 Mar 16;118(11):e2015874118
    Antigenic cartography reveals complexities of genetic determinants that lead to antigenic differences among pandemic GII.4 noroviruses.
    Kendra JA, Tohma K, Ford-Siltz LA, Lepore CJ, Parra GI
  12. Gut Microbes 2021 Mar 30;13(1):1-13
    Understanding the relationship between norovirus diversity and immunity.
    A Ford-Siltz L, Tohma K, I Parra G
  13. EClinicalMedicine 2020 Oct 5;27:100561
    Norovirus-specific immunoglobulin A in breast milk for protection against norovirus-associated diarrhea among infants.
    Labayo HKM, Pajuelo MJ, Tohma K, Ford-Siltz LA, Gilman RH, Cabrera L, Mayta H, Sanchez GJ, Cornejo AT, Bern C, Dapat C, Nochi T, Parra GI, Oshitani H, Saito M
  14. Viruses 2020 May 7;12(5):516
    Genomic analyses of human sapoviruses detected over a 40-year period reveal disparate patterns of evolution among genotypes and genome regions.
    Tohma K, Kulka M, Coughlan S, Green KY, Parra GI
  15. Emerg Infect Dis 2020 Jan;26(1):157-9
    Recombinant nontypeable genotype II human noroviruses in the Americas.
    Tohma K, Lepore CJ, Degiuseppe JI, Stupka JA, Saito M, Mayta H, Zimic M, Ford-Siltz LA, Gilman RH, Parra GI
  16. Infect Genet Evol 2019 Nov;75:103991
    Analysis of GII.P7 and GII.6 noroviruses circulating in Italy during 2011-2016 reveals a replacement of lineages and complex recombination history.
    Diakoudi G, Lanave G, Catella C, Medici MC, De Conto F, Calderaro A, Loconsole D, Chironna M, Bonura F, Giammanco GM, Banyai K, Tohma K, Parra GI, Martella V, De Grazia S
  17. J Gen Virol 2019 Oct;100(10):1393-406
    Updated classification of norovirus genogroups and genotypes.
    Chhabra P, de Graaf M, Parra GI, Chan MC, Green K, Martella V, Wang Q, White PA, Katayama K, Vennema H, Koopmans MPG, Vinje J
  18. MBio 2019 Sep 24;10(5):e02202-19
    Population genomics of GII.4 noroviruses reveal complex diversification and new antigenic sites involved in the emergence of pandemic strains.
    Tohma K, Lepore CJ, Gao Y, Ford-Siltz LA, Parra GI
  19. Virus Evol 2019 Jul;5(2):vez048
    Emergence of norovirus strains: a tale of two genes.
    Parra GI
  20. Clin Infect Dis 2019 May 30;68(12):2067-78
    Neutralizing antibody responses to homologous and heterologous H1 and H3 influenza A strains after vaccination with inactivated trivalent influenza vaccine vary with age and prior year vaccination.
    Wang W, Chen Q, Ford-Siltz LA, Katzelnick LC, Parra GI, Song HS, Vassell R, Weiss CD
  21. Viruses 2019 Mar;11(3):204
    Genomics analyses of GIV and GVI noroviruses reveal the distinct clustering of human and animal viruses.
    Ford-Siltz LA, Mullis L, Sanad YM, Tohma K, Lepore CJ, Azevedo M, Parra GI
  22. J Gen Virol 2018 Aug;99(8):1027-35
    Evolutionary dynamics of non-GII genotype 4 (GII.4) noroviruses reveal limited and independent diversification of variants.
    Tohma K, Lepore CJ, Ford-Siltz LA, Parra GI
  23. Cell Host Microbe 2018 Aug 8;24(2):208-20
    Vesicle-cloaked virus clusters are optimal units for inter-organismal viral transmission.
    Santiana M, Ghosh S, Ho BA, Rajasekaran V, Du WL, Mutsafi Y, De Jesus-Diaz DA, Sosnovtsev SV, Levenson EA, Parra GI, Takvorian PM, Cali A, Bleck C, Vlasova AN, Saif LJ, Patton JT, Lopalco P, Corcelli A, Green KY, Altan-Bonnet N
  24. Genome Announc 2018 Mar 8;6(10):e00095-18
    Complete genome sequence of a nontypeable GII norovirus detected in Peru.
    Tohma K, Saito M, Mayta H, Zimic M, Lepore CJ, Ford-Siltz LA, Gilman RH, Parra GI
  25. Open Forum Infect Dis 2017 Oct;4(4):ofx236
    Sequential gastroenteritis outbreaks in a single year caused by norovirus genotypes GII.2 and GII.6 in an institutional setting.
    Karangwa CK, Parra GI, Bok K, Johnson JA, Levenson EA, Green KY
  26. mSphere 2017 Jun;2(3):e00187-17
    Phylogenetic analyses suggest that factors other than the capsid protein play a role in the epidemic potential of GII.2 norovirus.
    Tohma K, Lepore CJ, Ford-Siltz LA, Parra GI
  27. Epidemiol Infect 2017 Jun;145(8):1591-6
    A large outbreak of acute gastroenteritis in Shippensburg, Pennsylvania, 1972 revisited: evidence for common source exposure to a recombinant GII.Pg/GII.3 norovirus.
    Johnson JA, Parra GI, Levenson EA, Green KY
  28. MBio 2017 Feb 14;8(1):e00031-17
    Identification of human junctional adhesion molecule 1 as a functional receptor for the Hom-1 calicivirus on human cells.
    Sosnovtsev SV, Sandoval-Jaime C, Parra GI, Tin CM, Jones RW, Soden J, Barnes D, Freeth J, Smith AW, Green KY
  29. Infect Genet Evol 2017 Jan;47:121-4
    Detection of novel GII.17 norovirus in Argentina, 2015.
    Degiuseppe JI, Gomes KA, Hadad MF, Parra GI, Stupka JA
  30. PLoS Pathog 2017 Jan 19;13(1):e1006136
    Static and evolving norovirus genotypes: implications for epidemiology and immunity.
    Parra GI, Squires RB, Karangwa CK, Johnson JA, Lepore C, Sosnovtsev SV, Green KY

 

 
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