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
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:
- determine the antigenic relationship among the different norovirus genotypes;
- develop new tools to better understand the rules governing the emergence and diversification of pandemic noroviruses;
- 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.
Publications
- 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 - 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 - 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 - 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 - 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 - Virus Evol 2019 Jul;5(2):vez048
Emergence of norovirus strains: a tale of two genes.
Parra GI - 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 - 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 - 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 - 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 - 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 - mSphere 2017 May-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 - 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 - 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