Humoral correlates of protection against influenza A H3N2 virus infection.

BACKGROUND: Influenza virus remains a threat to human health, but gaps remain in our knowledge of the humoral correlates of protection against influenza virus A/H3N2, limiting our ability to generate effective, broadly protective vaccines. The role of antibodies against the hemagglutinin (HA) stalk, a highly conserved but immunologically sub-dominant region, has not been established for influenza virus A/H3N2. METHODS: Household transmission studies were conducted in Managua, Nicaragua across three influenza seasons. Household contacts were tested for influenza virus infection using RT-PCR. We compared pre-existing antibody levels against full-length hemagglutinin (FLHA), HA stalk, and neuraminidase (NA) measured by enzyme-linked immunosorbent assay (ELISA), along with HA inhibition assay (HAI) titers, between infected and uninfected participants. RESULTS: A total of 899 individuals participated in household activation, with 329 infections occurring. A four-fold increase in initial HA stalk titers was independently associated with an 18% decrease in the risk of infection (OR=0.82, 95%CI 0.68-0.98, p=0.04). In adults, anti-HA stalk antibodies were independently associated with protection (OR=0.72, 95%CI 0.54-0.95, p=0.02). However, in 0-14-year-olds, anti-NA antibodies (OR=0.67, 95%CI 0.53-0.85, p<0.01) were associated with protection against infection, but anti-HA stalk antibodies were not. CONCLUSIONS: The HA stalk is an independent correlate of protection against A/H3N2 infection, though this association is age dependent. Our results support the continued exploration of the HA stalk as a target for broadly protective influenza vaccines but suggest that the relative benefits may depend on age and influenza virus exposure history.

Interim Estimates of 2023-24 Seasonal Influenza Vaccine Effectiveness - United States.

In the United States, annual influenza vaccination is recommended for all persons aged ≥6 months. Using data from four vaccine effectiveness (VE) networks during the 2023-24 influenza season, interim influenza VE was estimated among patients aged ≥6 months with acute respiratory illness-associated medical encounters using a test-negative case-control study design. Among children and adolescents aged 6 months-17 years, VE against influenza-associated outpatient visits ranged from 59% to 67% and against influenza-associated hospitalization ranged from 52% to 61%. Among adults aged ≥18 years, VE against influenza-associated outpatient visits ranged from 33% to 49% and against hospitalization from 41% to 44%. VE against influenza A ranged from 46% to 59% for children and adolescents and from 27% to 46% for adults across settings. VE against influenza B ranged from 64% to 89% for pediatric patients in outpatient settings and from 60% to 78% for all adults across settings. These findings demonstrate that the 2023-24 seasonal influenza vaccine is effective at reducing the risk for medically attended influenza virus infection. CDC recommends that all persons aged ≥6 months who have not yet been vaccinated this season get vaccinated while influenza circulates locally.

Infection-Induced Immunity Is Associated With Protection Against Severe Acute Respiratory Syndrome Coronavirus 2 Infection and Decreased Infectivity.

BACKGROUND: The impact of infection-induced immunity on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission has not been well established. Here we estimate the effects of prior infection induced immunity in adults and children on SARS-CoV-2 transmission in households. METHODS: We conducted a household cohort study from March 2020-November 2022 in Managua, Nicaragua; following a housheold SARS-CoV-2 infection, household members are closely monitored for infection. We estimate the association of time period, age, symptoms, and prior infection with secondary attack risk. RESULTS: Overall, transmission occurred in 70.2% of households, 40.9% of household contacts were infected, and the secondary attack risk ranged from 8.1% to 13.9% depending on the time period. Symptomatic infected individuals were more infectious (rate ratio [RR] 21.2, 95% confidence interval [CI]: 7.4-60.7) and participants with a prior infection were half as likely to be infected compared to naïve individuals (RR 0.52, 95% CI:.38-.70). In models stratified by age, prior infection was associated with decreased infectivity in adults and adolescents (secondary attack risk [SAR] 12.3, 95% CI: 10.3, 14.8 vs 17.5, 95% CI: 14.8, 20.7). However, although young children were less likely to transmit, neither prior infection nor symptom presentation was associated with infectivity. During the Omicron era, infection-induced immunity remained protective against infection. CONCLUSIONS: Infection-induced immunity is associated with decreased infectivity for adults and adolescents. Although young children are less infectious, prior infection and asymptomatic presentation did not reduce their infectivity as was seen in adults. As SARS-CoV-2 transitions to endemicity, children may become more important in transmission dynamics.

Burden and seasonality of primary and secondary symptomatic common cold coronavirus infections in Nicaraguan children.

BACKGROUND: The current SARS-CoV-2 pandemic highlights the need for an increased understanding of coronavirus epidemiology. In a pediatric cohort in Nicaragua, we evaluate the seasonality and burden of common cold coronavirus (ccCoV) infection and evaluate likelihood of symptoms in reinfections. METHODS: Children presenting with symptoms of respiratory illness were tested for each of the four ccCoVs (NL63, 229E, OC43, and HKU1). Annual blood samples collected before ccCoV infection were tested for antibodies against each ccCoV. Seasonality was evaluated using wavelet and generalized additive model (GAM) analyses, and age-period effects were investigated using a Poisson model. We also evaluate the risk of symptom presentation between primary and secondary infections. RESULTS: In our cohort of 2576 children from 2011 to 2016, we observed 595 ccCoV infections and 107 cases of ccCoV-associated lower respiratory infection (LRI). The overall incidence rate was 61.1 per 1000 person years (95% confidence interval (CI): 56.3, 66.2). Children under two had the highest incidence of ccCoV infections and associated LRI. ccCoV incidence rapidly decreases until about age 6. Each ccCoV circulated throughout the year and demonstrated annual periodicity. Peaks of NL63 typically occurred 3 months before 229E peaks and 6 months after OC43 peaks. Approximately 69% of symptomatic ccCoV infections were secondary infections. There was slightly lower risk (rate ratio (RR): 0.90, 95% CI: 0.83, 0.97) of LRI between secondary and primary ccCoV infections among participants under the age of 5. CONCLUSIONS: ccCoV spreads annually among children with the greatest burden among ages 0-1. Reinfection is common; prior infection is associated with slight protection against LRI among the youngest children.

High Co-circulation of Influenza and Severe Acute Respiratory Syndrome Coronavirus 2.

In the first 2 years of the coronavirus disease 2019 pandemic, influenza transmission decreased substantially worldwide, meaning that health systems were not faced with simultaneous respiratory epidemics. In 2022, however, substantial influenza transmission returned to Nicaragua where it co-circulated with severe acute respiratory syndrome coronavirus 2, causing substantial disease burden.

Infection-induced immunity is associated with protection against SARS-CoV-2 infection, but not decreased infectivity during household transmission.

Background: Understanding the impact of infection-induced immunity on SARS-CoV-2 transmission will provide insight into the transition of SARS-CoV-2 to endemicity. Here we estimate the effects of prior infection induced immunity and children on SARS-CoV-2 transmission in households. Methods: We conducted a household cohort study between March 2020-June 2022 in Managua, Nicaragua where when one household member tests positive for SARS-CoV-2, household members are closely monitored for SARS-CoV-2 infection. Using a pairwise survival model, we estimate the association of infection period, age, symptoms, and infection-induced immunity with secondary attack risk. Results: Overall transmission occurred in 72.4% of households, 42% of household contacts were infected and the secondary attack risk was 13.0% (95% CI: 11.7, 14.6). Prior immunity did not impact the probability of transmitting SARS-CoV-2. However, participants with pre-existing infection-induced immunity were half as likely to be infected compared to naïve individuals (RR 0.53, 95% CI: 0.39, 0.72), but this reduction was not observed in children. Likewise, symptomatic infected individuals were more likely to transmit (RR 24.4, 95% CI: 7.8, 76.1); however, symptom presentation was not associated with infectivity of young children. Young children were less likely to transmit SARS-CoV-2 than adults. During the omicron era, infection-induced immunity remained protective against infection. Conclusions: Infection-induced immunity is associated with protection against infection for adults and adolescents. While young children are less infectious, prior infection and asymptomatic presentation did not reduce their infectivity as was seen in adults. As SARS-CoV-2 transitions to endemicity, children may become more important in transmission dynamics. Article summary: Infection-induced immunity protects against SARS-CoV-2 infection for adolescents and adults; however, there was no protection in children. Prior immunity in an infected individual did not impact the probability they will spread SARS-CoV-2 in a household setting.

High co-circulation of influenza and SARS-CoV-2.

In the first two years of the COVID-19 pandemic, influenza transmission decreased substantially worldwide meaning that health systems were not faced with simultaneous respiratory epidemics. In 2022, however, substantial influenza transmission returned to Nicaragua where it co-circulated with SARS-CoV-2 causing substantial disease burden.

SARS-CoV-2 and endemic coronaviruses: Comparing symptom presentation and severity of symptomatic illness among Nicaraguan children.

It has been proposed that as SARS-CoV-2 transitions to endemicity, children will represent the greatest proportion of SARS-Co-V-2 infections as they currently do with endemic coronavirus infections. While SARS-CoV-2 infection severity is low for children, it is unclear if SARS-CoV-2 infections are distinct in symptom presentation, duration, and severity from endemic coronavirus infections in children. We compared symptom risk and duration of endemic human coronavirus (HCoV) infections from 2011-2016 with SARS-CoV-2 infections from March 2020-September 2021 in a Nicaraguan pediatric cohort. Blood samples were collected from study participants annually in February-April. Respiratory samples were collected from participants that met testing criteria. Blood samples collected in were tested for SARS-CoV-2 antibodies and a subset of 2011-2016 blood samples from four-year-old children were tested for endemic HCoV antibodies. Respiratory samples were tested for each of the endemic HCoVs from 2011-2016 and for SARS-CoV-2 from 2020-2021 via rt-PCR. By April 2021, 854 (49%) cohort participants were ELISA positive for SARS-CoV-2 antibodies. Most participants had antibodies against one alpha and one beta coronavirus by age four. We observed 595 symptomatic endemic HCoV infections from 2011-2016 and 121 symptomatic with SARS-CoV-2 infections from March 2020-September 2021. Symptom presentation of SARS-CoV-2 infection and endemic coronavirus infections were very similar, and SARS-CoV-2 symptomatic infections were as or less severe on average than endemic HCoV infections. This suggests that, for children, SARS-CoV-2 may be just another endemic coronavirus. However, questions about the impact of variants and the long-term effects of SARS-CoV-2 remain.

Association of SARS-CoV-2 Seropositivity and Symptomatic Reinfection in Children in Nicaragua.

Importance: The impact of the SARS-CoV-2 pandemic on children remains unclear. Better understanding of the burden of COVID-19 among children and their risk of reinfection is crucial, as they will be among the last groups vaccinated. Objective: To characterize the burden of COVID-19 and assess how risk of symptomatic reinfection may vary by age among children. Design, Setting, and Participants: In this prospective, community-based pediatric cohort study conducted from March 1, 2020, to October 15, 2021, 1964 nonimmunocompromised children aged 0 to 14 years were enrolled by random selection from the Nicaraguan Pediatric Influenza Cohort, a community-based cohort in District 2 of Managua, Nicaragua. Additional newborn infants aged 4 weeks or younger were randomly selected and enrolled monthly via home visits. Exposures: Prior COVID-19 infection as confirmed by positive anti-SARS-CoV-2 antibodies (receptor binding domain and spike protein) or real-time reverse transcriptase-polymerase chain reaction (RT-PCR)-confirmed COVID-19 infection at least 60 days before current COVID-19 infection. Main Outcomes and Measures: Symptomatic COVID-19 cases confirmed by real-time RT-PCR and hospitalization within 28 days of symptom onset of a confirmed COVID-19 case. Results: This cohort study assessed 1964 children (mean [SD] age, 6.9 [4.4] years; 985 [50.2%] male). Of 1824 children who were tested, 908 (49.8%; 95% CI, 47.5%-52.1%) were seropositive during the study. There were also 207 PCR-confirmed COVID-19 cases, 12 (5.8%) of which were severe enough to require hospitalization. Incidence of COVID-19 was highest among children younger than 2 years (16.1 cases per 100 person-years; 95% CI, 12.5-20.5 cases per 100 person-years), which was approximately 3 times the incidence rate in any other child age group assessed. In addition, 41 symptomatic SARS-CoV-2 episodes (19.8%; 95% CI, 14.4%-25.2%) were reinfections. Conclusions and Relevance: In this prospective, community-based pediatric cohort study, rates of symptomatic and severe COVID-19 were highest among the youngest participants, with rates stabilizing at approximately 5 years of age. In addition, symptomatic reinfections represented a large proportion of symptomatic COVID-19 cases.

Burden of SARS-CoV-2 and protection from symptomatic second infection in children.

IMPORTANCE: The impact of the SARS-CoV-2 pandemic on children remains unclear. Better understanding of the burden of COVID-19 among children and their protection against re-infection is crucial as they will be among the last groups vaccinated. OBJECTIVE: To characterize the burden of COVID-19 and assess how protection from symptomatic re-infection among children may vary by age. DESIGN: A prospective, community-based pediatric cohort study conducted from March 1, 2020 through October 15, 2021. SETTING: The Nicaraguan Pediatric Influenza Cohort is a community-based cohort in District 2 of Managua, Nicaragua. PARTICIPANTS: A total of 1964 children aged 0-14 years participated in the cohort. Non-immunocompromised children were enrolled by random selection from a previous pediatric influenza cohort. Additional newborn infants aged ≤4 weeks were randomly selected and enrolled monthly, via home visits. EXPOSURES: Prior COVID-19 infection as confirmed by positive anti SARS-CoV-2 antibodies (receptor binding domain [RBD] and spike protein) or real time RT-PCR confirmed COVID-19 infection ≥60 days prior to current COVID-19. MAIN OUTCOMES AND MEASURES: Symptomatic COVID-19 cases confirmed by real time RT-PCR and hospitalization within 28 days of symptom onset of confirmed COVID-19 case. RESULTS: Overall, 49.8% of children tested were seropositive over the course of the study. There were also 207 PCR-confirmed COVID-19 cases, 12 (6.4%) of which were severe enough to require hospitalization. Incidence of COVID-19 was highest among children aged <2 years-16.1 per 100 person-years (95% Confidence Interval [CI]: 12.5, 20.5)-approximately three times that of children in any other age group assessed. Additionally, 41 (19.8%) symptomatic SARS-CoV-2 episodes were re-infections, with younger children slightly more protected against symptomatic reinfection. Among children aged 6-59 months, protection was 61% (Rate Ratio [RR]:0.39, 95% CI:0.2,0.8), while protection among children aged 5-9 and 10-14 years was 64% (RR:0.36,0.2,0.7), and 49% (RR:0.51,0.3-0.9), respectively. CONCLUSIONS AND RELEVANCE: In this prospective community-based pediatric cohort rates of symptomatic and severe COVID-19 were highest among the youngest participants, with rates stabilizing around age 5. Reinfections represent a large proportion of PCR-positive cases, with children <10 years displaying greater protection from symptomatic reinfection. A vaccine for children <5 years is urgently needed. KEY POINTS: Question: What is the burden of COVID-19 among young children and how does protection from re-infection vary with age?Findings: In this study of 1964 children aged 0-14 years children <5 years had the highest rates of symptomatic and severe COVID-19 while also displaying greater protection against re-infection compared to children ≥10 years.Meaning: Given their greater risk of infection and severe disease compared to older children, effective vaccines against COVID-19 are urgently needed for children under 5.

SARS-CoV-2 and endemic coronaviruses: Comparing symptom presentation and severity of symptomatic illness among Nicaraguan children.

It has been proposed that as SARS-CoV-2 transitions to endemicity, children will represent the greatest proportion of SARS-Co-V-2 infections as they currently do with endemic coronavirus infections. While SARS-CoV-2 infection severity is low for children, it is unclear if SARS-CoV-2 infections are distinct in symptom presentation, duration, and severity from endemic coronavirus infections in children. We compared symptom risk and duration of endemic human coronavirus (HCoV) infections from 2011-2016 with SARS-CoV-2 infections from March 2020-September 2021 in a Nicaraguan pediatric cohort. Blood samples were collected from study participants annually in February-April. Respiratory samples were collected from participants that met testing criteria. Blood samples collected in were tested for SARS-CoV-2 antibodies and a subset of 2011-2016 blood samples from four-year-old children were tested for endemic HCoV antibodies. Respiratory samples were tested for each of the endemic HCoVs from 2011-2016 and for SARS-CoV-2 from 2020-2021 via rt-PCR. By April 2021, 854 (49%) cohort participants were ELISA positive for SARS-CoV-2 antibodies. Most participants had antibodies against one alpha and one beta coronavirus by age four. We observed 595 symptomatic endemic HCoV infections from 2011-2016 and 121 symptomatic with SARS-CoV-2 infections from March 2020-September 2021. Symptom presentation of SARS-CoV-2 infection and endemic coronavirus infections were very similar, and SARS-CoV-2 symptomatic infections were as or less severe on average than endemic HCoV infections. This suggests that, for children, SARS-CoV-2 may be just another endemic coronavirus. However, questions about the impact of variants and the long-term effects of SARS-CoV-2 remain.

Symptoms, Infection Duration, and Hemagglutinin Inhibition Antibody Response in Influenza A Infections.

BACKGROUND: Many influenza studies assume that symptomatic and asymptomatic cases have equivalent antibody responses. METHODS: This study examines the relationship between influenza symptoms and serological response. Influenza-positive index cases and household members in Managua, Nicaragua, during 2012-2017 were categorized by symptom status. RESULTS: Antibody response was assessed using hemagglutination inhibition assays (HAI). Among 510 cases, 74.5% had ≥4-fold increase in HAI antibodies, and 75.3% had febrile illness. In a logistic regression model, febrile cases had 2.17 times higher odds of a ≥4-fold titer rise compared to asymptomatic cases (95% confidence interval, 1.02-4.64). CONCLUSIONS: Studies relying on serological assays may not generalize to asymptomatic infections.

Ecological Evidence for Lower Risk of Lymphoma with Greater Exposure to Sunlight and Higher Altitude.

Introduction: Sunlight exposure increases vitamin D-related immune modulation and motility of T lymphocytes. Blue light exposure from the sun can stimulate immune function and help promote healthy circadian rhythm. Hence, greater sunlight exposure may lower the risk of Hodgkin lymphoma and non-Hodgkin lymphoma (NHL). Altitude may also lower the risk of these cancers through an oxygen-related mechanism, and because cosmic radiation has less shield from the atmosphere at higher levels, it allows for radiation hormesis. Methods: An ecological study design was used, with county-level lymphoma, sunlight, altitude, urban residency, poverty, smoking, obesity, and leisure-time physical inactivity data for 16 cancer registries (607 counties) in the contiguous United States, 2012-2016. Relative rate estimates were derived from two-level mixed effects Poisson regression models. Results: Higher rates of NHL are associated with being older, male, and white. Higher rates of Hodgkin lymphoma are associated with ages 20 years and older, male, and white or black. The risk of NHL or Hodgkin lymphoma is lower among those living in poverty. Urban residency, smoking, obesity, and physical inactivity are not associated with these cancers. Both increased sunlight exposure and higher altitude are simultaneously associated with lower rates of Hodgkin lymphoma and NHL in adjusted models. The inverse association between sunlight and NHL is more pronounced with higher altitude. The inverse association between sunlight and Hodgkin lymphoma is only in altitudes below 500 m. Conclusions: Greater sunlight exposure and higher altitude are simultaneously associated with lower rates of Hodgkin lymphoma and NHL. The inverse associations are dependent on altitude, with the relationship only in lower altitudes for Hodgkin lymphoma and more pronounced in higher altitude for NHL.

Modeling the effects of atmospheric pressure on suicide rates in the USA using geographically weighted regression.

Low atmospheric pressure may increase depression and suicide through inducing hypoxia. Previous studies have not evaluated the geographic variation of this relationship across the United States. Analyses were based on three groupings of age-adjusted completed suicide rates (all suicide, firearm-related suicide, non-firearm-related suicide) from 2286 counties in the United States. Multiple regression was used to determine the overall relationship between atmospheric pressure and completed suicide rates. Geographically weighted regression (GWR) models were used to obtain local coefficient estimates. A negative correlation between atmospheric pressure and completed suicide rates was observed for all three suicide groupings (p-value <0.0001). Significant, negative GWR coefficient estimates were located in the West and Northeast for the all suicides and firearm-related suicides, and in the Midwest for non-firearm-related suicides.

Reduced Lung Cancer Mortality With Lower Atmospheric Pressure.

BACKGROUND: Research has shown that higher altitude is associated with lower risk of lung cancer and improved survival among patients. The current study assessed the influence of county-level atmospheric pressure (a measure reflecting both altitude and temperature) on age-adjusted lung cancer mortality rates in the contiguous United States, with 2 forms of spatial regression. METHODS: Ordinary least squares regression and geographically weighted regression models were used to evaluate the impact of climate and other selected variables on lung cancer mortality, based on 2974 counties. RESULTS: Atmospheric pressure was significantly positively associated with lung cancer mortality, after controlling for sunlight, precipitation, PM2.5 (µg/m3), current smoker, and other selected variables. Positive county-level ß coefficient estimates (P < .05) for atmospheric pressure were observed throughout the United States, higher in the eastern half of the country. CONCLUSION: The spatial regression models showed that atmospheric pressure is positively associated with age-adjusted lung cancer mortality rates, after controlling for other selected variables.