A non-human primate model for human norovirus infection.

Norovirus infection can cause gastrointestinal disease in humans. Development of therapies and vaccines against norovirus have been limited by the lack of a suitable and reliable animal model. Here we established rhesus macaques as an animal model for human norovirus infection. We show that rhesus macaques are susceptible to oral infection with human noroviruses from two different genogroups. Variation in duration of virus shedding (days to weeks) between animals, evolution of the virus over the time of infection, induction of virus-specific adaptive immune responses, susceptibility to reinfection and preferential replication of norovirus in the jejunum of rhesus macaques was similar to infection reported in humans. We found minor pathological signs and changes in epithelial cell surface glycosylation patterns in the small intestine during infection. Detection of viral protein and RNA in intestinal biopsies confirmed the presence of the virus in chromogranin A-expressing epithelial cells, as it does in humans. Thus, rhesus macaques are a promising non-human primate model to evaluate vaccines and therapeutics against norovirus disease.

Prototype Pathogens for Vaccine and Monoclonal Antibody Countermeasure Development: NIAID Workshop Process and Outcomes for Viral Families of Pandemic Potential.

Given the increased risk of pandemics driven by emerging and reemerging infectious diseases, it is imperative that the United States and global scientific community be better prepared for future threats by prioritizing and launching key research programs and strategies. In December 2021, the National Institute of Allergy and Infectious Diseases (NIAID) published its pandemic preparedness plan, which focuses on the prototype pathogen approach for medical countermeasure development. The plan was introduced before its release at a NIAID-hosted workshop in November 2021 that featured scientific experts from the extramural community, government, and the private sector and focused on selection of prototype pathogens from 10 viral families with pandemic risk and moderate resources. This article will serve as an introduction to this special issue and will briefly define the prototype pathogen approach, describe the workshop goals and process for outcomes, and provide an outline of the viral working group articles to follow and future directions for NIAID.

Safety of COVID-19 vaccines during pregnancy: A systematic review and meta-analysis.

BACKGROUND: Assessment of COVID-19 vaccines safety during pregnancy is urgently needed. METHODS: We conducted a systematic review and meta-analysis to evaluate the safety of COVID-19 vaccines, including their components and technological platforms used in other vaccines during pregnancy and animal studies to complement direct evidence. We searched literature databases from its inception to September 2021 without language restriction, COVID-19 vaccine websites, and reference lists of other systematic reviews and the included studies. Pairs of reviewers independently selected, data extracted, and assessed the risk of bias of the studies. Discrepancies were resolved by consensus. (PROSPERO CRD42021234185). RESULTS: We retrieved 8,837 records from the literature search; 71 studies were included, involving 17,719,495 pregnant persons and 389 pregnant animals. Most studies (94%) were conducted in high-income countries, were cohort studies (51%), and 15% were classified as high risk of bias. We identified nine COVID-19 vaccine studies, seven involving 309,164 pregnant persons, mostly exposed to mRNA vaccines. Among non-COVID-19 vaccines, the most frequent exposures were AS03 and aluminum-based adjuvants. A meta-analysis of studies that adjusted for potential confounders showed no association with adverse outcomes, regardless of the vaccine or the trimester of vaccination. Neither the reported rates of adverse pregnancy outcomes nor reactogenicity exceeded expected background rates, which was the case for ASO3- or aluminum-adjuvanted non-COVID-19 vaccines in the proportion meta-analyses of uncontrolled studies/arms. The only exception was postpartum hemorrhage after COVID-19 vaccination (10.40%; 95% CI: 6.49-15.10%), reported by two studies; however, the comparison with non-exposed pregnant persons, available for one study, found non-statistically significant differences (adjusted OR 1.09; 95% CI 0.56-2.12). Animal studies showed consistent results with studies in pregnant persons. CONCLUSION: We found no safety concerns for currently administered COVID-19 vaccines during pregnancy. Additional experimental and real-world evidence could enhance vaccination coverage. Robust safety data for non-mRNA-based COVID-19 vaccines are still needed.

Safety, immunogenicity, and effectiveness of COVID-19 vaccines for pregnant persons: A protocol for systematic review and meta analysis.

INTRODUCTION: Numerous vaccines have been evaluated and approved for coronavirus disease 2019 (COVID-19). Since pregnant persons have been excluded from most clinical trials of COVID-19 vaccines, sufficient data regarding the safety of these vaccines for the pregnant person and their fetus have rarely been available at the time of product licensure. However, as COVID-19 vaccines have been deployed, data on the safety, reactogenicity, immunogenicity, and efficacy of COVID-19 vaccines for pregnant persons and neonates are becoming increasingly available. A living systematic review and meta-analysis of the safety and effectiveness of COVID-19 vaccines for pregnant persons and newborns could provide the information necessary to help guide vaccine policy decisions. METHODS AND ANALYSIS: We aim to conduct a living systematic review and meta-analysis based on biweekly searches of medical databases (e.g., MEDLINE, EMBASE, CENTRAL) and clinical trial registries to systematically identify relevant studies of COVID-19 vaccines for pregnant persons. Pairs of reviewers will independently select, extract data, and conduct risk of bias assessments. We will include randomized clinical trials, quasi-experimental studies, cohort, case-control, cross-sectional studies, and case reports. Primary outcomes will be the safety, efficacy, and effectiveness of COVID-19 vaccines in pregnant persons, including neonatal outcomes. Secondary outcomes will be immunogenicity and reactogenicity. We will conduct paired meta-analyses, including prespecified subgroup and sensitivity analyses. We will use the grading of recommendations assessment, development, and evaluation approach to evaluate the certainty of evidence.

Prototype Pathogen Approach for Vaccine and Monoclonal Antibody Development: A Critical Component of the NIAID Plan for Pandemic Preparedness.

Severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) emerged 20 years ago, presaging a series of subsequent infectious disease epidemics of international concern. The recent emergence of SARS-CoV-2 has underscored the importance of targeted preparedness research to enable rapid countermeasure development during a crisis. In December 2021 the National Institute of Allergy and Infectious Diseases (NIAID), building upon the successful strategies developed during the SARS-CoV-2 response and to prepare for future pandemics, published a pandemic preparedness plan that outlined a research strategy focused on priority pathogens, technology platforms, and prototype pathogens. To accelerate the discovery, development, and evaluation of medical countermeasures against new or previously unknown pathogens of pandemic potential, we present here a strategy of research directed at select prototype pathogens. In this manner, leveraging a prototype pathogen approach may serve as a powerful cornerstone in biomedical research preparedness to protect public health from newly emerging and reemerging infectious diseases.

An introduction to the Marburg virus vaccine consortium, MARVAC.

The emergence of Marburg virus (MARV) in Guinea and Ghana triggered the assembly of the MARV vaccine "MARVAC" consortium representing leaders in the field of vaccine research and development aiming to facilitate a rapid response to this infectious disease threat. Here, we discuss current progress, challenges, and future directions for MARV vaccines.

Multi-site observational maternal and infant COVID-19 vaccine study (MOMI-vax): a study protocol.

BACKGROUND: Pregnant women were excluded from investigational trials of COVID-19 vaccines. Limited data are available to inform pregnant and postpartum women on their decisions to receive a COVID-19 vaccine. METHODS: The goal of this observational, prospective cohort study is to evaluate the immunogenicity and safety of various Emergency Use Authorization (EUA) or licensed COVID-19 vaccines administered to pregnant or lactating women and describe the transplacental antibody transfer and kinetics of antibodies in mothers and infants. The study is adaptive, allowing additional groups to be added as new vaccines or vaccine regimens are authorized. Up to 20 clinical research institutions in the United States (U.S.) will be included. Approximately 200 pregnant women and 65 postpartum women will be enrolled per EUA or licensed COVID-19 vaccine formulation in the U.S. This study will include pregnant and postpartum women of all ages with and without chronic medical conditions. Their infants will be enrolled and followed beginning at birth in the pregnant cohort and beginning at the earliest possible time point in the postpartum cohort. Blood samples will be collected for immunogenicity outcomes and pregnancy and birth outcomes assessed among women and infants. Primary analyses will be descriptive and done by vaccine type and/or platform. DISCUSSION: Given the long-standing and legitimate challenges of enrolling pregnant individuals into clinical trials early in the vaccine development pipeline, this study protocol describes our current study and provides a template to inform the collection of data for pregnant individuals receiving COVID-19 or other vaccines. TRIAL REGISTRATION: NCT05031468 .

Safety of components and platforms of COVID-19 vaccines considered for use in pregnancy: A rapid review.

BACKGROUND: Rapid assessment of COVID-19 vaccine safety during pregnancy is urgently needed. METHODS: We conducted a rapid systematic review, to evaluate the safety of COVID-19 vaccines selected by the COVID-19 Vaccines Global Access-Maternal Immunization Working Group in August 2020, including their components and their technological platforms used in other vaccines for pregnant persons. We searched literature databases, COVID-19 vaccine pregnancy registries, and explored reference lists from the inception date to February 2021 without language restriction. Pairs of reviewers independently selected studies through COVIDENCE, and performed the data extraction and the risk of bias assessment. Discrepancies were resolved by consensus. Registered on PROSPERO (CRD42021234185). RESULTS: We retrieved 6757 records and 12 COVID-19 pregnancy registries from the search strategy; 38 clinical and non-clinical studies (involving 2,398,855 pregnant persons and 56 pregnant animals) were included. Most studies (89%) were conducted in high-income countries and were cohort studies (57%). Most studies (76%) compared vaccine exposures with no exposure during the three trimesters of pregnancy. The most frequent exposure was to AS03 adjuvant, in the context of A/H1N1 pandemic influenza vaccines, (n = 24) and aluminum-based adjuvants (n = 11). Only one study reported exposure to messenger RNA in lipid nanoparticles COVID-19 vaccines. Except for one preliminary report about A/H1N1 influenza vaccination (adjuvant AS03), corrected by the authors in a more thorough analysis, all studies concluded that there were no safety concerns. CONCLUSION: This rapid review found no evidence of pregnancy-associated safety concerns of COVID-19 vaccines or of their components or platforms when used in other vaccines. However, the need for further data on several vaccine platforms and components is warranted, given their novelty. Our findings support current WHO guidelines recommending that pregnant persons may consider receiving COVID-19 vaccines, particularly if they are at high risk of exposure or have comorbidities that enhance the risk of severe disease.

Accelerated COVID-19 vaccine development: milestones, lessons, and prospects.

The development of effective vaccines to combat infectious diseases is a complex multi-year and multi-stakeholder process. To accelerate the development of vaccines for coronavirus disease 2019 (COVID-19), a novel pathogen emerging in late 2019 and spreading globally by early 2020, the United States government (USG) mounted an operation bridging public and private sector expertise and infrastructure. The success of the endeavor can be seen in the rapid advanced development of multiple vaccine candidates, with several demonstrating efficacy and now being administered around the globe. Here, we review the milestones enabling the USG-led effort, the methods utilized, and ensuing outcomes. We discuss the current status of COVID-19 vaccine development and provide a perspective for how partnership and preparedness can be better utilized in response to future public-health pandemic emergencies.

Safety of COVID-19 vaccines, their components or their platforms for pregnant women: A rapid review.

BACKGROUND: Pregnant women with COVID-19 are at an increased risk of severe COVID-19 illness as well as adverse pregnancy and birth outcomes. Many countries are vaccinating or considering vaccinating pregnant women with limited available data about the safety of this strategy. Early identification of safety concerns of COVID-19 vaccines, including their components, or their technological platforms is therefore urgently needed. METHODS: We conducted a rapid systematic review, as the first phase of an ongoing full systematic review, to evaluate the safety of COVID-19 vaccines in pregnant women, including their components, and their technological platforms (whole virus, protein, viral vector or nucleic acid) used in other vaccines, following the Cochrane methods and the PRISMA statement for reporting (PROSPERO-CRD42021234185).We searched literature databases, COVID-19 and pregnancy registries from inception February 2021 without time or language restriction and explored the reference lists of relevant systematic reviews retrieved. We selected studies of any methodological design that included at least 50 pregnant women or pregnant animals exposed to the vaccines that were selected for review by the COVAX MIWG in August 2020 or their components or platforms included in the COVID-19 vaccines, and evaluated adverse events during pregnancy and the neonatal period.Pairs of reviewers independently selected studies through the COVIDENCE web software and performed the data extraction through a previously piloted online extraction form. Discrepancies were resolved by consensus. RESULTS: We identified 6768 records, 256 potentially eligible studies were assessed by full-text, and 37 clinical and non-clinical studies (38 reports, involving 2,397,715 pregnant women and 56 pregnant animals) and 12 pregnancy registries were included.Most studies (89%) were conducted in high-income countries. The most frequent study design was cohort studies (n=21), followed by surveillance studies, randomized controlled trials, and registry analyses. Most studies (76%) allowed comparisons between vaccinated and unvaccinated pregnant women (n=25) or animals (n=3) and reported exposures during the three trimesters of pregnancy.The most frequent exposure was to AS03 adjuvant in the context of A/H1N1 pandemic influenza vaccines (n=24), followed by aluminum-based adjuvants (n=11). Aluminum phosphate was used in Respiratory Syncytial Virus Fusion candidate vaccines (n=3) and Tdap vaccines (n=3). Different aluminum-based adjuvants were used in hepatitis vaccines. The replication-deficient simian adenovirus ChAdOx1 was used for a Rift Valley fever vaccine. Only one study reported exposure to messenger RNA (mRNA) COVID-19 vaccines that also used lipid nanoparticles. Except for one preliminary report about A/H1N1 influenza vaccination (adjuvant AS03) - corrected by the authors in a more thorough analysis, all studies concluded that there were no safety concerns. CONCLUSION: This rapid review found no evidence of pregnancy-associated safety concerns of COVID-19 vaccines that were selected for review by the COVAX MIWG or of their components or platforms when used in other vaccines. However, the need for further data on several vaccine platforms and components is warranted given their novelty. Our findings support current WHO guidelines recommending that pregnant women may consider receiving COVID-19 vaccines, particularly if they are at high risk of exposure or have comorbidities that enhance the risk of severe disease.

Genetic associations with a fever after measles-containing vaccines.

Children have elevated fever risk 1 to 2 weeks after the first dose of a measles-containing vaccine (MCV), which is likely affected by genetic, immunologic, and clinical factors. Fever after MCV is associated with febrile seizures, though may also be associated with higher measles antibody titers. This exploratory study investigated genetic and immunologic associations with a fever after MCV. Concurrent with a randomized Phase 3 clinical trial of 12-15-month-olds who received their first measles-mumps-rubella (MMR) vaccine in which parents recorded post-vaccination temperatures daily, we consented a subset to collect additional blood and performed human leukocyte antigens (HLA) typing. Association between fever 5-12 days after MMR ("MMR-associated") and HLA type was assessed using logistic regression. We compared 42-day post-vaccination geometric mean titers (GMT) to measles between children who did and did not have fever using a t-test. We enrolled 86 children and performed HLA typing on 82; 13 (15.1%) had MMR-associated fever. Logistic regressions identified associations between MMR-associated fever and HLA Class I loci A-29:02 (P = .036), B-57:01 (P = .018), C-06:02 (P = .006), C-14:02 (P = .022), and Class II loci DRB1-15 (P = .045). However, Bonferroni's adjustment for multiple comparisons suggests that these associations could have been due to chance. Ninety-eight percent of children had protective antibody titers to measles; however, GMT was higher among those with fever compared with children without fever (P = .006). Fever after the measles vaccine correlated with genetic factors and higher immune response. This study suggests a possible genetic susceptibility to MMR-associated fever.

Parental risk factors for fever in their children 7-10 days after the first dose of measles-containing vaccines.

We evaluated whether parental clinical conditions were associated with fever after a first dose of measles-containing vaccine (MCV) in the child in a cohort study including 244,125 children born in Kaiser Permanente Northern California between 2009 and 2016 who received MCV between ages 1 and 2 years. Each child was linked with his/her mother and father when possible. Parental clinical conditions present before and after their child's birth were identified. We defined fever in the children as clinic and emergency department visits with a fever code 7-10 days after a first dose of MCV ("MCV-associated fever"). We evaluated parental clinical conditions associated with MCV-associated fever using multivariate logistic regression analyses. After adjusting for multiple factors, including healthcare utilization, maternal fever [odds ratio (OR) = 1.19, 95% confidence interval (CI) 1.06-1.32], fever after MCV (OR = 5.90, 95% CI 1.35-25.78), respiratory infections (OR = 1.20, 95% CI 1.10-1.31), migraine (OR = 1.14, 95% CI 1.05-1.24), syncope (OR 1.14, 95% CI 1.01-1.27), and essential thrombocythemia (OR = 1.93, 95% CI 1.15-3.25) were significantly associated with MCV-associated fever. Paternal respiratory infections (OR = 1.15, 95% CI 1.05-1.27), fever associated with respiratory infections (OR = 1.47, 95% CI 1.23-1.76), and vitiligo (OR = 1.63, 95% CI 1.06-2.53) were significantly associated with MCV-associated fever. Parental clinical conditions, specifically fever alone and fever associated with respiratory infection, are associated with fever in their child 7-10 days after MCV.

Development of an Intervention to Reduce Pain and Prevent Syncope Related to Adolescent Vaccination.

INTRODUCTION: There is a lack of research into the perspectives of patients, parents, and clinicians regarding strategies for vaccine-related pain and syncope prevention that may improve the adolescent vaccination experience and encourage future vaccination. OBJECTIVE: To develop an intervention on the basis of preference for strategies to reduce pain and prevent syncope associated with adolescent vaccination. METHODS: We conducted focus groups and interviews with 8 recently vaccinated Kaiser Permanente Northwest (KPNW) members aged 11 to 17 years and their parents to explore perceptions of pain and syncope after vaccination as well as receptivity to potential interventions. Additionally, we interviewed 7 clinical staff who routinely vaccinate children. We conducted content analysis to identify promising interventions and conducted a data synthesis workshop to select a final intervention for piloting. RESULTS: All participants expressed willingness to use previsit education, breathing exercises, social support or distraction, and water consumption. Patients and parents expressed a need for verbal education and messaging about potential vaccine-related outcomes, and clinicians noted a need to identify patients who are anxious before a vaccination visit. Most participants suggested a "comfort menu" intervention, to include comfort and distraction items that medical staff offer adolescents before and during vaccination. CONCLUSION: Patients, parents, and clinicians acknowledged the value of interventions to reduce pain and syncope after adolescent vaccination. Stakeholders identified a comfort menu as the intervention to be piloted at 2 KPNW pediatric clinics. Further research is needed to test the effectiveness of the "Vaccination Comfort Menu" intervention in improving vaccination experiences and continued receipt of vaccinations.

Malaria vaccine trials in pregnant women: An imperative without precedent.

Pregnant women are highly susceptible to Plasmodium falciparum malaria, leading to substantial maternal, perinatal, and infant mortality. While malaria vaccine development has made significant progress in recent years, no trials of malaria vaccines have ever been conducted in pregnant women. In December 2016, an expert meeting was convened at NIAID, NIH, in Rockville, Maryland to deliberate on the rationale and design of malaria vaccine trials in pregnant women. The discussions highlighted the progress made over recent years in the field of maternal immunization for other infectious diseases, and the evolving regulatory and ethical environment, all of which support a new emphasis on testing malaria vaccines that offer direct benefits to pregnant women. Initial safety and immunogenicity studies of malaria vaccines will be conducted in non-pregnant adult volunteers. Subsequently, efficacy trials involving pregnant women will likely be conducted in malaria-endemic and often resource-poor environments where sufficiently high malaria incidence will allow vaccine activity to be measured. Such trials will need to meet all international standards to ensure the safety of mother and offspring, under oversight of appropriate ethical and regulatory bodies. The convened experts drafted a clinical development plan to test a malaria vaccine product during pregnancy, using as a case study PfSPZ Vaccine being developed by Sanaria Inc. that is currently in phase 2 testing. Following the expert recommendations, a pregnancy registry has been initiated in Ouelessebougou, Mali, to provide baseline information on maternal and fetal outcomes as a context for evaluating PfSPZ Vaccine safety in the future, and new regimens are being assessed that will be suitable for evaluation in pregnant women.

Defining the interval for monitoring potential adverse events following immunization (AEFIs) after receipt of live viral vectored vaccines.

Live viral vectors that express heterologous antigens of the target pathogen are being investigated in the development of novel vaccines against serious infectious agents like HIV and Ebola. As some live recombinant vectored vaccines may be replication-competent, a key challenge is defining the length of time for monitoring potential adverse events following immunization (AEFI) in clinical trials and epidemiologic studies. This time period must be chosen with care and based on considerations of pre-clinical and clinical trials data, biological plausibility and practical feasibility. The available options include: (1) adapting from the current relevant regulatory guidelines; (2) convening a panel of experts to review the evidence from a systematic literature search to narrow down a list of likely potential or known AEFI and establish the optimal risk window(s); and (3) conducting "near real-time" prospective monitoring for unknown clustering's of AEFI in validated large linked vaccine safety databases using Rapid Cycle Analysis for pre-specified adverse events of special interest (AESI) and Treescan to identify previously unsuspected outcomes. The risk window established by any of these options could be used along with (4) establishing a registry of clinically validated pre-specified AESI to include in case-control studies. Depending on the infrastructure, human resources and databases available in different countries, the appropriate option or combination of options can be determined by regulatory agencies and investigators.

Feasibility of a pilot intervention to reduce pain and syncope during adolescent vaccination.

PURPOSE: Vaccines recommended for adolescents are considered safe and effective, however administration may occasionally result in acute pain at the injection site or syncope (fainting). These adverse effects pose a risk to patient safety and are potential barriers to adherence to future vaccinations. We assessed a novel intervention designed to help prevent acute pain and syncope associated with adolescent vaccinations. METHODS: We conducted a 3-month pilot study to assess the feasibility and acceptability of a vaccination comfort menu within two Kaiser Permanente Northwest pediatric clinics. The menu offered a variety of comfort items (e.g., cold packs, squeeze balls) that children could select prior to their vaccination. We surveyed parents of recently vaccinated adolescents and interviewed providers to assess the implementation and effectiveness of the intervention. RESULTS: Response rate for the parent survey was 33% (378/1136). Only 20% of the parents reported that their provider offered the comfort menu during the vaccination visit. Approximately 50% of the adolescents who were offered the menu selected a comfort item and most of these participants reported that the item was very (35%) or somewhat (38%) helpful in improving their vaccination experience. Per provider interviews, common barriers to implementing the intervention included lack of time and convenience, and the brevity of the pilot period. CONCLUSIONS: The comfort menu may improve the vaccination experience of youth and increase the likelihood of adherence with future vaccinations. However, only 20% of the parents reported that their provider offered the menu during the vaccination visit. Additional research is needed to determine the feasibility of implementing this intervention on a larger scale, as well as assessing whether the intervention has a significant impact on reducing adverse events.

No association between influenza vaccination during pregnancy and adverse birth outcomes.

BACKGROUND: Pregnant women are recommended to receive inactivated influenza vaccination anytime during pregnancy. Studies have investigated the impact of influenza vaccination during pregnancy on birth outcomes and results on preterm birth have been inconsistent. METHODS: We conducted a retrospective cohort study among children born at a gestational age≥24weeks from January 1, 2010 to December 31, 2015 at Kaiser Permanente Northern California facilities (KPNC). We evaluated the association between maternal influenza vaccination during pregnancy and risk of preterm birth, small and large for gestational age, admission to the neonatal intensive care unit (NICU), respiratory distress syndrome, low birth weight, and low Apgar score. We ascertained the dates of maternal influenza vaccination, conception, and delivery, as well as birth outcomes from KPNC inpatient and outpatient databases. Conditional multivariate Cox regression and logistic regression analyses were used to determine the association between maternal vaccination during pregnancy and risk of each birth outcome. RESULTS: The study included 145,869 children. Maternal influenza vaccination during pregnancy was not associated with risk of small or large for gestational age births, preterm birth, need for mechanical ventilation at birth, respiratory distress syndrome, admission to the NICU, low birth weight, or low Apgar score. However, when we did not control for immortal time bias, the risk of preterm birth (odds ratio [OR]=0.69, 95% confidence interval [CI] 0.66-0.72) was lower among infants of vaccinated mothers. CONCLUSION: We found no association between maternal influenza vaccination during pregnancy and adverse birth outcomes. When investigating preterm birth outcome in association with vaccination during pregnancy, immortal time bias should be taken into account in the analysis.

Sequential Gastroenteritis Outbreaks in a Single Year Caused by Norovirus Genotypes GII.2 and GII.6 in an Institutional Setting.

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 2 sequential gastroenteritis outbreaks that occurred in 1971 at the former Henryton State Hospital in Maryland. Approximately 40% of the resident population experienced clinical symptoms in both outbreaks, which occurred 11 months apart. METHODS: Stored stools and paired sera were re-analyzed to investigate the etiology of the 2 outbreaks. RESULTS: Different norovirus genotypes were identified as the etiological agents responsible for the illnesses, with GII.2 associated with the first outbreak and GII.6 with the second. The viruses were antigenically distinct as determined by analyses of hyperimmune sera raised against the corresponding virus-like particles in animals, as well as paired sera from infected individuals. CONCLUSIONS: The observed antigenic differences were consistent with the failure of the GII.2 strain to provide cross-protective immunity to the GII.6 strain a few months later. An understanding of antigenic diversity among norovirus genotypes will be important in the design of norovirus vaccines.