Assessment of Humoral Immune Responses to Repeated Influenza Vaccination in a Multiyear Cohort: A 5-Year Follow-up.

The long-term effects of host factors on vaccine-elicited immune responses have not been well studied, and the interactions of host factors with annual influenza vaccinations are yet to be explored. We analyzed data from a cohort of 386 individuals who received the standard-dose influenza vaccine and enrolled in ≥2 seasons from 2016 to 2020. Our analyses indicated disparate vaccine-elicited immune responses between males and females in adults when they were repeatedly vaccinated for at least 2 seasons. Notably, we found interactive effects between age and body mass index (BMI) on overall immune responses, and between sex at birth and BMI in adults.

If Long-Term Suppression is not Possible, how do we Minimize Mortality for Infectious Disease Outbreaks?

OBJECTIVE: For any emerging pathogen, the preferred approach is to drive it to extinction with non-pharmaceutical interventions (NPI) or suppress its spread until effective drugs or vaccines are available. However, this might not always be possible. If containment is infeasible, the best people can hope for is pathogen transmission until population level immunity is achieved, with as little morbidity and mortality as possible. METHODS: A simple computational model was used to explore how people should choose NPI in a non-containment scenario to minimize mortality if mortality risk differs by age. RESULTS: Results show that strong NPI might be worse overall if they cannot be sustained compared to weaker NPI of the same duration. It was also shown that targeting NPI at different age groups can lead to similar reductions in the total number of infected, but can have strong differences regarding the reduction in mortality. CONCLUSIONS: Strong NPI that can be sustained until drugs or vaccines become available are always preferred for preventing infection and mortality. However, if people encounter a worst-case scenario where interventions cannot be sustained, allowing some infections to occur in lower-risk groups might lead to an overall greater reduction in mortality than trying to protect everyone equally.

A data-driven semi-parametric model of SARS-CoV-2 transmission in the United States.

To support decision-making and policy for managing epidemics of emerging pathogens, we present a model for inference and scenario analysis of SARS-CoV-2 transmission in the USA. The stochastic SEIR-type model includes compartments for latent, asymptomatic, detected and undetected symptomatic individuals, and hospitalized cases, and features realistic interval distributions for presymptomatic and symptomatic periods, time varying rates of case detection, diagnosis, and mortality. The model accounts for the effects on transmission of human mobility using anonymized mobility data collected from cellular devices, and of difficult to quantify environmental and behavioral factors using a latent process. The baseline transmission rate is the product of a human mobility metric obtained from data and this fitted latent process. We fit the model to incident case and death reports for each state in the USA and Washington D.C., using likelihood Maximization by Iterated particle Filtering (MIF). Observations (daily case and death reports) are modeled as arising from a negative binomial reporting process. We estimate time-varying transmission rate, parameters of a sigmoidal time-varying fraction of hospitalized cases that result in death, extra-demographic process noise, two dispersion parameters of the observation process, and the initial sizes of the latent, asymptomatic, and symptomatic classes. In a retrospective analysis covering March-December 2020, we show how mobility and transmission strength became decoupled across two distinct phases of the pandemic. The decoupling demonstrates the need for flexible, semi-parametric approaches for modeling infectious disease dynamics in real-time.

Use of Patient-Reported Symptom Data in Clinical Decision Rules for Predicting Influenza in a Telemedicine Setting.

INTRODUCTION: Increased use of telemedicine could potentially streamline influenza diagnosis and reduce transmission. However, telemedicine diagnoses are dependent on accurate symptom reporting by patients. If patients disagree with clinicians on symptoms, previously derived diagnostic rules may be inaccurate. METHODS: We performed a secondary data analysis of a prospective, nonrandomized cohort study at a university student health center. Patients who reported an upper respiratory complaint were required to report symptoms, and their clinician was required to report the same list of symptoms. We examined the performance of 5 previously developed clinical decision rules (CDRs) for influenza on both symptom reports. These predictions were compared against PCR diagnoses. We analyzed the agreement between symptom reports, and we built new predictive models using both sets of data. RESULTS: CDR performance was always lower for the patient-reported symptom data, compared with clinician-reported symptom data. CDRs often resulted in different predictions for the same individual, driven by disagreement in symptom reporting. We were able to fit new models to the patient-reported data, which performed slightly worse than previously derived CDRs. These models and models built on clinician-reported data both suffered from calibration issues. DISCUSSION: Patients and clinicians frequently disagree about symptom presence, which leads to reduced accuracy when CDRs built with clinician data are applied to patient-reported symptoms. Predictive models using patient-reported symptom data performed worse than models using clinician-reported data and prior results in the literature. However, the differences are minor, and developing new models with more data may be possible.

Effect of Norovirus Inoculum Dose on Virus Kinetics, Shedding, and Symptoms.

The effect of norovirus dose on outcomes such as virus shedding and symptoms after initial infection is not well understood. We performed a secondary analysis of a human challenge study by using Bayesian mixed-effects models. As the dose increased from 4.8 to 4,800 reverse transcription PCR units, the total amount of shed virus in feces increased from 4.5 × 1011 to 3.4 × 1012 genomic equivalent copies; in vomit, virus increased from 6.4 × 105 to 3.0 × 107 genomic equivalent copies. Onset time of viral shedding in feces decreased from 1.4 to 0.8 days, and time of peak viral shedding decreased from 2.3 to 1.5 days. Time to symptom onset decreased from 1.5 to 0.8 days. One type of symptom score increased. An increase in norovirus dose was associated with more rapid shedding and symptom onset and possibly increased severity. However, the effect on virus load and shedding was inconclusive.

COVID-19 Transmission Dynamics Among Close Contacts of Index Patients With COVID-19: A Population-Based Cohort Study in Zhejiang Province, China.

Importance: Much remains unknown about the transmission dynamics of COVID-19. How the severity of the index case and timing of exposure is associated with disease in close contacts of index patients with COVID-19 and clinical presentation in those developing disease is not well elucidated. Objectives: To investigate the association between the timing of exposure and development of disease among close contacts of index patients with COVID-19 and to evaluate whether the severity of the index case is associated with clinical presentation in close contacts who develop COVID-19. Design, Setting, and Participants: This study used a large, population-based cohort of 730 individuals (index patients) who received a diagnosis of COVID-19 in Zhejiang Province, China, from January 8 to July 30, 2020, along with a contact tracing surveillance program. Field workers visited 8852 close contacts of the index patients and evaluated them for COVID-19 through August 2020. A timeline was constructed to characterize different exposure periods between index patients and their contacts. Main Outcomes and Measures: The primary outcome was the attack rate of COVID-19, defined as the total number of new COVID-19 cases diagnosed among contacts of index patients divided by the total number of exposed contacts. A secondary outcome was asymptomatic clinical presentation among infected contacts. Relative risks were calculated to investigate risk factors for COVID-19 among contacts and asymptomatic clinical presentation among infected contacts. Results: Among 8852 close contacts (4679 male contacts [52.9%]; median age, 41 years [interquartile range, 28-54 years]) of 730 index patients (374 male patients [51.2%]; median age, 46 years [interquartile range, 36-56 years]), contacts were at highest risk of COVID-19 if they were exposed between 2 days before and 3 days after the index patient's symptom onset, peaking at day 0 (adjusted relative risk [ARR], 1.3; 95% CI, 1.2-1.5). Compared with being exposed to an asymptomatic index patient, the risk of COVID-19 among contacts was higher when they were exposed to index patients with mild (ARR, 4.0; 95% CI, 1.8-9.1) and moderate (ARR, 4.3; 95% CI, 1.9-9.7) cases of COVID-19. As index case severity increased, infected contacts were less likely to be asymptomatic (exposed to patient with mild COVID-19: ARR, 0.3; 95% CI, 0.1-0.9; exposed to patient with moderate COVID-19: ARR, 0.3; 95% CI, 0.1-0.8). Conclusions and Relevance: This cohort study found that individuals with COVID-19 were most infectious a few days before and after symptom onset. Infected contacts of asymptomatic index patients were less likely to present with COVID-19 symptoms, suggesting that quantity of exposure may be associated with clinical presentation in close contacts.

Community drivers of tuberculosis diagnostic delay in Kampala, Uganda: a retrospective cohort study.

BACKGROUND: Recent approaches to TB control have focused on identifying and treating active cases to halt further transmission. Patients with TB symptoms often delay to seek care, get appropriate diagnosis, and initiate effective treatment. These delays are partly influenced by whom the patients contact within their community network. We aimed to evaluate the community drivers of diagnostic delay in an urban setting in Uganda. METHODS: In this study we analyze data from a retrospective cohort of 194 TB patients in Kampala, Uganda. We characterized the patterns of contacts made by patients seeking care for TB symptoms. The main outcome of interest was total community contact delay, defined as the time patients spent seeking care before visiting a provider capable of diagnosing TB. RESULTS: Visits to health providers without access to appropriate diagnostic services accounted for 56% of contacts made by cohort members, and were significantly associated with community contact delay, as were symptoms common to other prevalent illnesses, such as bone and joint pain. CONCLUSIONS: Education programs aimed at primary care providers, as well as other community members, may benefit case identification, by informing them of rarer symptoms of TB, potential for co-infections of TB and other prevalent diseases, and the availability of diagnostic services.

The impact of social distancing, contact tracing, and case isolation interventions to suppress the COVID-19 epidemic: A modeling study.

INTRODUCTION: Most countries are dependent on nonpharmaceutical public health interventions such as social distancing, contact tracing, and case isolation to mitigate COVID-19 spread until medicines or vaccines widely available. Minimal research has been performed on the independent and combined impact of each of these interventions based on empirical case data. METHODS: We obtained data from all confirmed COVID-19 cases from January 7th to February 22nd 2020 in Zhejiang Province, China, to fit an age-stratified compartmental model using human contact information before and during the outbreak. The effectiveness of social distancing, contact tracing, and case isolation was studied and compared in simulation. We also simulated a two-phase reopening scenario to assess whether various strategies combining nonpharmaceutical interventions are likely to achieve population-level control of a second-wave epidemic. RESULTS: Our study sample included 1,218 symptomatic cases with COVID-19, of which 664 had no inter-province travel history. Results suggest that 36.5 % (95 % CI, 12.8-57.1) of contacts were quarantined, and approximately five days (95 % CI, 2.2-11.0) were needed to detect and isolate a case. As contact networks would increase after societal and economic reopening, avoiding a second wave without strengthening nonpharmaceutical interventions compared to the first wave it would be exceedingly difficult. CONCLUSIONS: Continuous attention and further improvement of nonpharmaceutical interventions are needed in second-wave prevention. Specifically, contact tracing merits further attention.

Five approaches to the suppression of SARS-CoV-2 without intensive social distancing.

Initial efforts to mitigate transmission of SARS-CoV-2 relied on intensive social distancing measures such as school and workplace closures, shelter-in-place orders and prohibitions on the gathering of people. Other non-pharmaceutical interventions for suppressing transmission include active case finding, contact tracing, quarantine, immunity or health certification, and a wide range of personal protective measures. Here we investigate the potential effectiveness of these alternative approaches to suppression. We introduce a conceptual framework represented by two mathematical models that differ in strategy. We find both strategies may be effective, although both require extensive testing and work within a relatively narrow range of conditions. Generalized protective measures such as wearing face masks, improved hygiene and local reductions in density are found to significantly increase the effectiveness of targeted interventions.

A modeling study to inform screening and testing interventions for the control of SARS-CoV-2 on university campuses.

University administrators face decisions about how to safely return and maintain students, staff and faculty on campus throughout the 2020-21 school year. We developed a susceptible-exposed-infectious-recovered (SEIR) deterministic compartmental transmission model of SARS-CoV-2 among university students, staff, and faculty. Our goals were to inform planning at our own university, Emory University, a medium-sized university with around 15,000 students and 15,000 faculty and staff, and to provide a flexible modeling framework to inform the planning efforts at similar academic institutions. Control strategies of isolation and quarantine are initiated by screening (regardless of symptoms) or testing (of symptomatic individuals). We explored a range of screening and testing frequencies and performed a probabilistic sensitivity analysis. We found that among students, monthly and weekly screening can reduce cumulative incidence by 59% and 87%, respectively, while testing with a 2-, 4- and 7-day delay between onset of infectiousness and testing results in an 84%, 74% and 55% reduction in cumulative incidence. Smaller reductions were observed among staff and faculty. Community-introduction of SARS-CoV-2 onto campus may be controlled with testing, isolation, contract tracing and quarantine. Screening would need to be performed at least weekly to have substantial reductions beyond disease surveillance. This model can also inform resource requirements of diagnostic capacity and isolation/quarantine facilities associated with different strategies.

Longitudinal Assessment of Immune Responses to Repeated Annual Influenza Vaccination in a Human Cohort of Adults and Teenagers.

Background: The overall performance of a multiple component vaccine assessed by the vaccine-elicited immune responses across various strains in a repeated vaccination setting has not been well-studied, and the comparison between adults and teenagers is yet to be made. Methods: A human cohort study was conducted at the University of Georgia, with 140 subjects (86 adults and 54 teenagers) repeatedly vaccinated in the 2017/2018 and 2018/2019 influenza seasons. Host information was prospectively collected, and serum samples were collected before and after vaccination in each season. The association between host factors and repeated measures of hemagglutination inhibition (HAI) composite scores was assessed by generalized linear models with generalized estimating equations. Results: The mean HAI composite scores for the entire sample (t = 4.26, df = 139, p < 0.001) and the teenager group (t = 6.44, df = 53, p < 0.001) declined in the second season, while the changes in the adults were not statistically significant (t = -1.14, df = 85, p = 0.26). A mixture pattern of changes in both directions was observed in the adults when stratified by prior vaccination. In addition, the regression analysis suggested an interactive effect of age and BMI on the HAI composite scores in the overall population (beta = 0.005; 95% CI, 0.0008-0.01) and the adults (beta = 0.005; 95% CI, 0.0005-0.01). Conclusions: Our study found distinct vaccine-elicited immune responses between adults and teenagers when both were repeatedly vaccinated in consecutive years. An interactive effect of age and BMI on the HAI composite scores were identified in the overall population and the adults.

SARS-CoV-2 Viral and Serological Testing When College Campuses Reopen: Some Practical Considerations.

The coronavirus disease 2019 (COVID-19) pandemic prompted universities across the United States to close campuses in Spring 2020. Universities are deliberating whether, when, and how they should resume in-person instruction in Fall 2020. In this essay, we discuss some practical considerations for the use of 2 potentially useful control strategies based on testing: (1) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcriptase-polymerase chain reaction (RT-PCR) testing followed by case-patient isolation and quarantine of close contacts, and (2) serological testing followed by an "immune shield" approach, that is, low social distancing requirements for seropositive persons. The isolation of case-patients and quarantine of close contacts may be especially challenging, and perhaps prohibitively difficult, on many university campuses. The "immune shield" strategy might be hobbled by a low positive predictive value of the tests used in populations with low seroprevalence. Both strategies carry logistical, ethical, and financial implications. The main nonpharmaceutical interventions will remain methods based on social distancing (eg, capping class size) and personal protective behaviors (eg, universal facemask wearing in public space) until vaccines become available, or unless the issues discussed herein can be resolved in such a way that using mass testing as main control strategies becomes viable.

Effectiveness of neuraminidase inhibitors to prevent mortality in patients with laboratory-confirmed avian influenza A H7N9.

OBJECTIVES: Avian influenza virus A(H7N9) remains a threat to humans and has great potential to cause a pandemic in the foreseeable future. Antiviral treatment with neuraminidase inhibitors has been recommended to treat patients with H7N9 infection as early as possible, although evidence-based research on their effectiveness for H7N9 infection is lacking. METHODS: Data from all laboratory-confirmed cases of H7N9 infection in Zhejiang Province between 2013 and 2017 were retrieved, and time-dependent survival models were used to evaluate the effectiveness of treatment with neuraminidase inhibitors to reduce the risk of mortality. RESULTS: The final optimal model found no significant association (odds ratio 1.29, 95% confidence interval 0.78-2.15) between time to treatment with neuraminidase inhibitors and survival after controlling for age and white blood cell count. Sensitivity analyses with multiple imputation for missing data concurred with the primary analysis. CONCLUSIONS: No association was found between treatment with neuraminidase inhibitors and survival in patients with H7N9 infection using various adjusted models and sensitivity analyses of missing data imputations.

Associations Between Relative Viral Load at Diagnosis and Influenza A Symptoms and Recovery.

BACKGROUND: Rapid point-of-care polymerase chain reaction (PCR) diagnostic tests generally provide a qualitative result of positive or negative only. Additional information about the relative viral load could be calculated. Such quantitative information might be useful for making treatment decisions. METHODS: We enrolled students at a university health center who presented with cough and 1 additional flu-like symptom from December 2016 to February 2017. Data were collected before, during, and 5 days after the clinic visit. All those enrolled in the study received a point-of-care PCR test (cobas Liat). For those patients that tested positive for influenza A, we investigated correlations between the relative viral load and measures of disease severity and recovery. RESULTS: One hundred thirty-five students tested positive for influenza A. We found a positive correlation between viral load and body temperature. Time since symptom onset seemed to have a negative correlation but was not statistically significant. We did not find any correlations between viral load and overall symptom severity or outcomes related to recovery. CONCLUSIONS: Although we found a correlation between relative viral load and body temperature, for our study population of young, overall healthy adults, we did not find that relative viral load provided additional information that could help in determining treatment and disease outcomes. It could be that viral load does provide useful additional information for other groups of patients, such as young children or older adults. Further studies on those populations are warranted.

Community Outbreak Investigation of SARS-CoV-2 Transmission Among Bus Riders in Eastern China.

Importance: Evidence of whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), can be transmitted as an aerosol (ie, airborne) has substantial public health implications. Objective: To investigate potential transmission routes of SARS-CoV-2 infection with epidemiologic evidence from a COVID-19 outbreak. Design, Setting, and Participants: This cohort study examined a community COVID-19 outbreak in Zhejiang province. On January 19, 2020, 128 individuals took 2 buses (60 [46.9%] from bus 1 and 68 [53.1%] from bus 2) on a 100-minute round trip to attend a 150-minute worship event. The source patient was a passenger on bus 2. We compared risks of SARS-CoV-2 infection among at-risk individuals taking bus 1 (n = 60) and bus 2 (n = 67 [source patient excluded]) and among all other individuals (n = 172) attending the worship event. We also divided seats on the exposed bus into high-risk and low-risk zones according to the distance from the source patient and compared COVID-19 risks in each zone. In both buses, central air conditioners were in indoor recirculation mode. Main Outcomes and Measures: SARS-CoV-2 infection was confirmed by reverse transcription polymerase chain reaction or by viral genome sequencing results. Attack rates for SARS-CoV-2 infection were calculated for different groups, and the spatial distribution of individuals who developed infection on bus 2 was obtained. Results: Of the 128 participants, 15 (11.7%) were men, 113 (88.3%) were women, and the mean age was 58.6 years. On bus 2, 24 of the 68 individuals (35.3% [including the index patient]) received a diagnosis of COVID-19 after the event. Meanwhile, none of the 60 individuals in bus 1 were infected. Among the other 172 individuals at the worship event, 7 (4.1%) subsequently received a COVID-19 diagnosis. Individuals in bus 2 had a 34.3% (95% CI, 24.1%-46.3%) higher risk of getting COVID-19 compared with those in bus 1 and were 11.4 (95% CI, 5.1-25.4) times more likely to have COVID-19 compared with all other individuals attending the worship event. Within bus 2, individuals in high-risk zones had moderately, but nonsignificantly, higher risk for COVID-19 compared with those in the low-risk zones. The absence of a significantly increased risk in the part of the bus closer to the index case suggested that airborne spread of the virus may at least partially explain the markedly high attack rate observed. Conclusions and Relevance: In this cohort study and case investigation of a community outbreak of COVID-19 in Zhejiang province, individuals who rode a bus to a worship event with a patient with COVID-19 had a higher risk of SARS-CoV-2 infection than individuals who rode another bus to the same event. Airborne spread of SARS-CoV-2 seems likely to have contributed to the high attack rate in the exposed bus. Future efforts at prevention and control must consider the potential for airborne spread of the virus.

Five approaches to the suppression of SARS-CoV-2 without intensive social distancing.

Initial efforts to mitigate transmission of SARS-CoV-2 relied on intensive social distancing measures such as school and workplace closures, shelter-in-place orders, and prohibitions on the gathering of people. Other non-pharmaceutical interventions for suppressing transmission include active case finding, contact tracing, quarantine, immunity or health certification, and a wide range of personal protective measures. Here we investigate the potential effectiveness of these alternative approaches to suppression. We introduce a conceptual framework represented by two mathematical models that differ in strategy. We find both strategies may be effective, although both require extensive testing and work within a relatively narrow range of conditions. Generalized protective measures such as wearing face masks, improved hygiene, and local reductions in density are found to significantly increase the effectiveness of targeted interventions.