Gabriel Parra

U.S. Food and Drug Administration | FDA · Division of Viral Products

Noroviruses are major pathogens associated with acute gastroenteritis worldwide. Their RNA genomes are diverse, with two major genogroups (GI and GII) comprised of at least 28 genotypes associated with human disease. To elucidate mechanisms underlying norovirus diversity and evolution, we used a large-scale genomics approach to analyze human norovi...

To determine whether the norovirus strain GII.17 recently detected in Maryland, USA, (Hu/GII.17/Gaithersburg/2014/US) is spreading globally, we characterized the genome. High similarity with the norovirus GII.17 that caused recent outbreaks in Asia indicates that the same strain was present in the United States during the 2014–15 norovirus season (...

We investigated sequential episodes of acute norovirus gastroenteritis in a young child within an 11-month period. The infections were caused by 2 distinct genotypes (GII.4 and GII.6). Failure to achieve cross-protective immunity was linked to absence of an enduring and cross-reactive mucosal immune response, a critical consideration for vaccine de...

Rotaviruses are dynamic pathogens that have been shown to infect multiple species. In 2006, two G4P[6] rotavirus strains with porcine characteristics were detected in Santa Fe, Argentina. To further characterize and determine the origin of these strains, nearly the full length of their genome was sequenced. While most of the genome segments were fr...

Noroviruses, a major cause of acute gastroenteritis worldwide, present antigenic diversity that must be considered for the development of an effective vaccine. In this study, we explored approaches to increase the broad reactivity of virus-like particle (VLP) norovirus vaccine candidates. The immunogenicity of a GII.4 "Consensus" VLP that was engin...

Antibodies are thought to play a major role in protection against human norovirus infection. Mouse humoral responses closely mimic those of humans; thus, mouse models are used to characterize norovirus epitopes on the major viral capsid protein, VP1. We have developed a panel of mouse monoclonal antibodies (mAbs) produced against the last pandemic...

Background Noroviruses are an important viral cause of chronic diarrhea in immunocompromised individuals. Method We collected norovirus-positive stool samples (n=448) from immunocompromised patients (n=88) at the National Institutes of Health Clinical Research Center, U.S. from 2010-2022. We assessed clinical characteristics of the cohort, norovir...

Norovirus is a major cause of acute gastroenteritis; GII.4 is the predominant strain in humans. Recently, 2 new GII.4 variants, Hong Kong 2019 and San Francisco 2017, were reported. Characterization using GII.4 monoclonal antibodies and serum demonstrated different antigenic profiles for the new variants compared with historical variants.

Background Rapidly evolving RNA viruses, such as human norovirus, generate extraordinary sequence diversity, posing a significant challenge to vaccine design. This diversity, coupled with short-lasting natural immunity, leads to reinfection throughout one's lifetime. How reexposure shapes humoral immunity to future norovirus strains remains incompl...

Noroviruses are a major cause of acute gastroenteritis worldwide and can establish chronic infection in immunocompromised individuals. To investigate the mechanisms of norovirus evolution during chronic infection, we selected seven representative patients from a National Institutes of Health study cohort who sustained norovirus infection for period...

GII.4 noroviruses are the major cause of acute gastroenteritis in all age groups. This predominance has been attributed to the continued emergence of phylogenetically discrete variants that escape immune responses to previous infections.

Human noroviruses are the major viral cause of acute gastroenteritis around the world. Although norovirus symptoms are in most cases mild and self-limited, severe and prolonged symptoms can occur in the elderly and in immunocompromised individuals. Thus, there is a great need for the development of specific therapeutics that can help mitigate infec...

A paradigm of RNA viruses is their ability to mutate and escape from herd immunity. Because antibody responses are a major effector for viral immunity, antigenic sites are usually under strong diversifying pressure. Here, we use norovirus as a model to study mechanisms of antigenic diversification of non-enveloped, fast-evolving RNA viruses. We com...

Human noroviruses are the leading global cause of viral gastroenteritis. Attempts at developing effective vaccines and treatments against norovirus disease have been stymied by the extreme genetic diversity and rapid geographic distribution of these viruses. The emergence and replacement of predominantly circulating norovirus genotypes has primaril...

Norovirus is a major cause of acute gastroenteritis. Human noroviruses present >30 different genotypes, with a single genotype (GII.4) predominating worldwide. Concurrent outbreaks of norovirus are often associated with the emergence of new viruses. While different hypotheses have been presented, the source of new mutations in noroviruses is still...

Norovirus is a major cause of acute gastroenteritis worldwide. Over 30 different genotypes, mostly from genogroup I (GI) and II (GII), have been shown to infect humans. Despite three decades of genome sequencing, our understanding of the role of genomic diversification across continents and time is incomplete. To close the spatiotemporal gap of gen...

Significance The GII.4 genotype of human noroviruses accounts for the majority of gastroenteritis outbreaks worldwide. This predominance is characterized by the chronological emergence of new variants in response to immune pressure. We performed a comprehensive analysis on a large panel of GII.4 viruses to investigate the genetic determinants of an...

Human noroviruses are the most common viral cause of acute gastroenteritis worldwide. Currently, there are no approved vaccines or specific therapeutics to treat the disease. Some obstacles delaying the development of a norovirus vaccine are: (i) the extreme diversity presented by noroviruses; (ii) our incomplete understanding of immunity to norovi...

Background: Norovirus (NV) causes acute gastroenteritis in infants. Humoral and fecal immunoglobulin A (IgA) responses have been correlated with protection against NV; however, the role of breast milk IgA against NV infection and associated diarrhea is still unknown. This study aimed to evaluate the protective role of NV-specific IgA (NV-IgA) in br...

Background Norovirus (NV) causes acute gastroenteritis in infants. Humoral and fecal immunoglobulin A (IgA) responses have been correlated with protection against NV; however, the role of breast milk IgA against NV infection and associated diarrhea is still unknown. This study aimed to evaluate the protective role of NV-specific IgA (NV-IgA) in bre...

Human sapovirus is a causative agent of acute gastroenteritis in all age groups. The use of full-length viral genomes has proven beneficial to investigate evolutionary dynamics and transmission chains. In this study, we developed a full-length genome sequencing platform for human sapovirus and sequenced the oldest available strains (collected in th...

Human noroviruses are the most common viral agents of acute gastroenteritis. Recently, human intestinal enteroids were shown to be permissive for norovirus infection. We tested their suitability as a system to study norovirus neutralization. Hyperimmune sera raised against virus-like particles (VLPs) representing different genotypes showed highly-s...

We report multiple nontypeable genotype II noroviruses circulating in South America; nucleotides differed by >25% from those of other genotypes. These viruses have been circulating in the Americas for ≈20 years and show recombination with other genotypes. Clues to norovirus natural history can guide development of treatment and prevention plans.

Noroviruses are a very diverse group of viruses that infect different mammalian species. In humans, norovirus is a major cause of acute gastroenteritis. Multiple norovirus infections can occur in a lifetime as the result of limited duration of acquired immunity and cross-protection among different strains. A combination of advances in sequencing me...

Noroviruses are an important cause of viral gastroenteritis around the world. An obstacle delaying the development of norovirus vaccines is inadequate understanding of the role of norovirus diversity in immunity. Using a population genomics approach, we identified new residues on the viral capsid protein (VP1) from GII.4 noroviruses, the predominan...

Noroviruses are genetically diverse RNA viruses associated with acute gastroenteritis in mammalian hosts. Phylogenetically, they can be segregated into different genogroups as well as P (polymerase)-groups and further into genotypes and P-types based on amino acid diversity of the complete VP1 gene and nucleotide diversity of the RNA-dependent RNA...

Noroviruses are important human enteric pathogens and monitoring their genetic diversity is important for epidemiological surveillance, vaccine development, and understanding of RNA viruses evolution. Epidemiological investigations have revealed that genogroup II, genotype 6 noroviruses (GII.6) are common agents of gastroenteritis. Upon sequencing...

GII.4 noroviruses are a major cause of acute gastroenteritis. Their dominance has been partially explained by the continuous emergence of antigenically distinct variants. To gain insights on the mechanisms of viral emergence and population dynamics of GII.4 noroviruses, we performed large-scale genomics, structural, and mutational analyses of the v...

Noroviruses are highly diverse viruses that are the major viral cause of acute gastroenteritis in humans. Although these viruses can infect multiple mammalian species, their potential for zoonosis is not well understood, especially within Genogroup IV (GIV), which contains viruses that infect humans, canines, and felines. The study of GIV viruses h...

Background: Prior influenza immunity influences homologous neutralizing antibody responses elicited by inactivated influenza vaccines (IIV), but neutralizing antibody responses to heterologous strains have not been extensively characterized. Methods: We analyzed neutralizing antibody titers in individuals ages 1-88 who received the 2009-2010 sea...

In enteric viral infections, such as those with rotavirus and norovirus, individual viral particles shed in stool are considered the optimal units of fecal-oral transmission. We reveal that rotaviruses and noroviruses are also shed in stool as viral clusters enclosed within vesicles that deliver a high inoculum to the receiving host. Cultured cells...

Noroviruses are extremely diverse, with ≥30 genotypes infecting humans. GII genotype 4 (GII.4) noroviruses, the most prevalent genotype, present a constant accumulation of mutations on the major capsid protein (VP1), resulting in the chronological emergence of new variants every 2-8 years. On the other hand, non-GII.4 noroviruses present a limited...

Norovirus, a leading cause of acute gastroenteritis in humans, is a highly diverse virus. Here, we report the complete genome sequence of a nontypeable genogroup II (GII) norovirus that was detected in a symptomatic Peruvian child in 2008. This virus showed low nucleotide sequence identities (≤82%) against all known genotypes.

Background Norovirus is a leading cause of acute gastroenteritis worldwide. Improved diagnostic capability has been instrumental in the characterization of archival norovirus strains associated with gastroenteritis outbreaks that were investigated decades ago. One such investigation was that of two sequential gastroenteritis outbreaks that occurred...

Rotavirus is the most common cause of acute diarrhea among infants and young children worldwide. Although rotaviruses pose a high burden in the Latin American population, massive rotavirus vaccination programs have been successfully implemented in this region. Extensive epidemiological analyses have shown that Latin American countries present a dif...

A luciferase immunoprecipitation systems (LIPS) assay was developed to define the antigenic specificity and titer of antibodies directed against human norovirus (HuNoV). Recombinant proteins, expressed by plasmid constructs encoding Renilla luciferase (Ruc) fused to the full-length HuNoV major capsid protein (VP1) (Ruc-antigen), were generated for...

Noroviruses are a major cause of gastroenteritis worldwide. Currently, there is no vaccine or specific antiviral available to treat norovirus disease. Multiple norovirus strains infect humans, but a single genotype (GII.4) has been regarded as the most important cause of viral gastroenteritis outbreaks worldwide. Its persistence and predominance ha...

Norovirus is the leading cause of acute gastroenteritis worldwide. For over two decades, a single genotype (GII.4) has been responsible for most norovirusassociated cases. However, during the winter of 2014 to 2015, the GII.4 strains were displaced by a rarely detected genotype (GII.17) in several countries of the Asian continent. Moreover, during...

Historical outbreaks can be an important source of information in the understanding of norovirus evolution and epidemiology. Here, we revisit an outbreak of undiagnosed gastroenteritis that occurred in Shippensburg, Pennsylvania in 1972. Nearly 5000 people fell ill over the course of 10 days. Symptoms included diarrhea, vomiting, stomach cramps, an...

The Hom-1 vesivirus was reported in 1998 following the inadvertent transmission of the animal calicivirus San Miguel sea lion virus to a human host in a laboratory. We characterized the Hom-1 strain and investigated the mechanism by which human cells could be infected. An expression library of 3,559 human plasma membrane proteins was screened for r...

Accumulation of mutations in GII.4 Den_Haag variants detected in Japan. (a) Full-length genome analyses showing the accumulation of nucleotide (upper figure) and amino acid (lower figure) mutations during three consecutive seasons in Japan [50, 51]. (b) Data from individual open reading frames (ORF) shows that ORF2 (encoding VP1) presents the lowes...

Matrix showing the frequency of re-infection and the genotypes detected. Data was obtained from studies that followed the natural history of norovirus infection [17, 18, 22, 38, 52–54]. Every possible combination was recorded from the re-infection cases. Re-infection with strains from the same immunotype are indicated by black cells. For immunotype...

Accumulation of mutations in VP1 during the shedding phase of an acute GII.4 infection in an immunocompetent individual. Four amino acid mutations at days 14 and 21 mapped into three major (A, C, and E) antigenic sites of GII.4 noroviruses. The GII.4 norovirus P domain was rendered using the previously solved crystal structure of norovirus VA387 (p...

Trees inferred by using the Maximum Likelihood method based on the Tamura-Nei model presented topologies similar to that shown by the Neighbor-joining method in Fig 5. (TIF)

Sequences of GII.6, GII.12 and GII.17 noroviruses used in this study. (DOCX)

Diversity in GII.12 viruses. (a) Phylogenetic trees showing the relationship of the different strains from the GII.12 genotype. Three variants (Clusters A-C) can be discriminated when nucleotides were used for tree reconstruction. No discrete variant was detected when amino acids were used. Trees were constructed using sequences encoding the VP1 an...

Norovirus ORF2 sequences used in the construction of trees representing the clustering of immunotypes. (DOCX)

During the winter of 2014–2015 a novel GII.17 norovirus strain emerged as a cause of large gastroenteritis outbreaks in Asia; displacing the long-term predominant strain, GII.4. Although sporadically detected, the emerging GII.17 virus was described in North America and Europe. In this study, we describe the presence of this novel strain in Argenti...

Background Noroviruses are a major cause of infectious gastroenteritis worldwide, and viruses can establish persistent infection in immunocompromised individuals. Risk factors and transmission in this population are not fully understood. Methods From 2010 through 2013, we conducted a retrospective review among immunocompromised patients (n = 268)...

Noroviruses are diverse positive-strand RNA viruses associated with acute gastroenteritis. Cross-reactive epitopes have been mapped primarily to conserved sequences in the capsid VP1 Shell (S) domain, and strain-specific epitopes to the highly variable Protruding (P) domain. In this work, we investigated a strain-specific linear epitope defined by...

The healthy human enteric tract is populated by a complex community of microbiota in synergistic balance with its host. Infection with a pathogenic virus can cause intestinal damage, inflammation, and diarrhea that alter the gut environment. The ability to diagnose pathogenic viruses rapidly and accurately is important in providing appropriate pati...

Rotavirus virions are formed by a three concentric protein layers that enclose the 11 double-stranded RNA (dsRNA) genome segments and the viral proteins VP1 and VP3. Interactions among the capsid proteins (VP2, VP6, VP7 and VP4) have been described to play a major role in viral fitness, while restricting the reassortment of the genomic segments dur...

Noroviruses are a major cause of acute gastroenteritis, but no vaccines or therapeutic drugs are available. Llama-derived single chain antibody fragments (also called VHH) are small, recombinant monoclonal antibodies of 15 kDa with several advantages over conventional antibodies. The aim of this study was to generate recombinant monoclonal VHH spec...

Technical Appendix. Differences in the major capsid protein among GII.7 noroviruses, phylogenetic relationships among GII.17 noroviruses circulating worldwide, and relationship of Hu/GII.17/Gaithersburg/2014/US with other GII.17 noroviruses.

Seasonal shifts in the predominant strains and the periodic emergence of new strains are epidemiological features of human rotaviruses. After the sporadic detection in two samples in 1998, G3P[8] strains reemerged as the predominant rotavirus during 2008-2009 in Argentina. Notably, in 2011 6.3% (37/587) of samples presented the G3P[6] genotypes, wh...

Group A rotaviruses are a major cause of severe gastroenteritis in children worldwide. Currently, two rotavirus vaccines are being used in vaccination programs, and one of the factors involved in lower vaccine efficacy is the mismatch among the circulating strains and the vaccine strains. Thus, the emergence of animal strains in the human populatio...

Feline calicivirus (FCV) is a common cause of mild to severe upper respiratory tract disease (URTD) in cats. FCV strain 21223 was isolated from a kitten with severe pneumonia in a disease outbreak with unusually high mortality (35 %) that occurred in a Missouri feline colony in 1995-1996. Phylogenetic analysis of the genome sequence of strain 21223...

Passive immunoprophylaxis or immunotherapy with norovirus-neutralizing monoclonal antibodies (MAbs) could be a useful treatment for high-risk populations including infants and young children, the elderly, and certain patients who are debilitated or immunocompromised. In order to obtain anti-norovirus MAbs with therapeutic potential, we stimulated a...

Noroviruses (NoV) have been shown to be an important cause of morbidity and mortality in children worldwide, only second after Group A rotaviruses (RVA). In Paraguay, acute gastroenteritis (AGE) is the third cause of mortality in children ≤5 years old. To analyze the presence and diversity of NoV in Paraguayan children ≤5 years old presenting AGE....

Noroviruses are major pathogens associated with acute gastroenteritis. They are diverse viruses, with at least six genogroups (GI-GVI) and multiple genotypes defined by differences in the major capsid protein, VP1. This diversity has challenged the development of broadly cross-reactive vaccines as well as efficient detection methods. Here, we repor...

a b s t r a c t Group A rotavirus (RVA) is one of the main causes of neonatal calf diarrhea worldwide. RVA strains affect-ing Argentinean cattle mainly possess combinations of the G6, G10, P[5] and P[11] genotypes. To deter-mine RVA diversity among Argentinean cattle, representative bovine RVA strains detected in diarrheic calves were selected from...

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