The evolutionary dynamics of influenza virus ultimately derive from processes that take place within and between infected individuals. Here we define influenza virus dynamics in human hosts through sequencing of 249 specimens from 200 individuals collected over 6290 person-seasons of observation. Because these viruses were collected from individuals in a prospective community-based cohort, they are broadly representative of natural infections with seasonal viruses. Consistent with a neutral model of evolution, sequence data from 49 serially sampled individuals illustrated the dynamic turnover of synonymous and nonsynonymous single nucleotide variants and provided little evidence for positive selection of antigenic variants. We also identified 43 genetically-validated transmission pairs in this cohort. Maximum likelihood optimization of multiple transmission models estimated an effective transmission bottleneck of 1–2 genomes. Our data suggest that positive selection is inefficient at the level of the individual host and that stochastic processes dominate the host-level evolution of influenza viruses.
Vaccine effectiveness estimates were lower than those demonstrated in other observational studies carried out during the same season. The unexpected findings of lower effectiveness with repeated vaccination and no protection given household exposure require further study.
Background
As part of the Household Influenza Vaccine Evaluation (HIVE) study, acute respiratory infections (ARI) have been identified in children and adults from 2010 to 2018.
Methods
Annually, 890 to 1441 individuals were followed and contacted weekly to report ARIs. Specimens collected during illness were tested for human coronaviruses (HCoV) types OC43, 229E, HKU1, and NL63.
Results
In total, 993 HCoV infections were identified during the 8 years, with OC43 most commonly seen and 229E the least. HCoVs were detected in a limited time period, between December and April/May and peaked in January/February. Highest infection frequency was in children <5 years (18 per 100 person-years), with little variation in older age groups (range, 7 to 11 per 100 person-years). Overall, 9% of adult cases and 20% of cases in children were associated with medical consultation. Of the 993 infections, 260 were acquired from an infected household contact. The serial interval between index and household-acquired cases ranged from 3.2 to 3.6 days and the secondary infection risk ranged from 7.2% to 12.6% by type.
Conclusions
Coronaviruses are sharply seasonal. They appear, based on serial interval and secondary infection risk, to have similar transmission potential to influenza A(H3N2) in the same population.
The term “original antigenic sin” was coined approximately 60 years ago to describe the imprinting by the initial first influenza A virus infection on the antibody response to subsequent vaccination. These studies did not suggest a reduction in the response to current antigens but instead suggested anamnestic recall of antibody to earlier influenza virus strains. Then, approximately 40 years ago, it was observed that sequential influenza vaccination might lead to reduced vaccine effectiveness (VE). This conclusion was largely dismissed after an experimental study involving sequential administration of then-standard influenza vaccines. Recent observations have provided convincing evidence that reduced VE after sequential influenza vaccination is a real phenomenon. We propose that such reduction in VE be termed “negative antigenic interaction,” given that there is no age cohort effect. In contrast, the potentially positive protective effect of early influenza virus infection later in life continues to be observed. It is essential that we understand better the immunologic factors underlying both original antigenic sin and negative antigenic interaction, to support development of improved influenza vaccines and vaccination strategies.
Longitudinal studies in families remain a valuable way to study respiratory infections. RT-PCR has increased the sensitivity of virus detection, including coinfecting viruses, and expanded our ability to detect viruses now known to cause ARI.
Despite substantial heterogeneity in pediatric trials, we found that treatment with oseltamivir significantly reduced the duration of illness in those with influenza and lowered the risk of developing otitis media. Alternative endpoints may be required to evaluate the efficacy of oseltamivir in pediatric patients with asthma.
Background
As of November 1, 2020, there have been more than 230K deaths and 9M confirmed and probable cases attributable to SARS-CoV-2 in the United States. However, this overwhelming toll has not been distributed equally, with geographic, race-ethnic, age, and socioeconomic disparities in exposure and mortality defining features of the U.S. COVID-19 epidemic.
Methods
We used individual-level COVID-19 incidence and mortality data from the U.S. state of Michigan to estimate age-specific incidence and mortality rates by race/ethnic group. Data were analyzed using hierarchical Bayesian regression models, and model results were validated using posterior predictive checks.
Results
In crude and age-standardized analyses we found rates of incidence and mortality more than twice as high than Whites for all groups except Native Americans. Blacks experienced the greatest burden of confirmed and probable COVID-19 infection (Age-standardized incidence = 1,626/100,000 population) and mortality (age-standardized mortality rate 244/100,000). These rates reflect large disparities, as Blacks experienced age-standardized incidence and mortality rates 5.5 (95% Posterior Credible Interval [CrI] = 5.4, 5.6) and 6.7 (95% CrI = 6.4, 7.1) times higher than Whites, respectively. We found that the bulk of the disparity in mortality between Blacks and Whites is driven by dramatically higher rates of COVID-19 infection across all age groups, particularly among older adults, rather than age-specific variation in case-fatality rates.
Conclusions
This work suggests that well-documented racial disparities in COVID-19 mortality in hard-hit settings, such as the U.S. state of Michigan, are driven primarily by variation in household, community and workplace exposure rather than case-fatality rates.
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