Increased Influenza Severity in Children in the Wake of SARS-CoV-2 (preprint)

The SARS-CoV-2 pandemic and subsequent interruption of influenza circulation has lowered population immunity to influenza, especially among children with few pre-pandemic exposures. We compared the incidence and severity of influenza A/H3N2 and influenza B/Victoria between 2022 and two pre-pandemic seasons and found an increased frequency of severe influenza in 2022.

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

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 naive 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.

High co-circulation of influenza and SARS-CoV-2 (preprint)

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 infection-induced immunity and the duration of viral shedding: results from a Nicaraguan household cohort study (preprint)

Background. Much of the worlds population has been infected with SARS-CoV-2. Thus, infection-induced immunity will play a critical role in future SARS-CoV-2 transmission. We investigated the impact of immunity from prior infection on viral shedding duration and viral load.Methods. We conducted a household cohort study in Managua, Nicaragua with an embedded transmission study that closely monitors participants regardless of symptom status. Real-time reverse-transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assays (ELISAs) were used to measure infections and seropositivity, respectively. Blood samples were collected in Feb/March and Oct/Nov 2020 and 2021, and surrounding household intensive monitoring periods. We used accelerated failure time models to compare shedding times. Participants vaccinated [≥]14 days prior to infection were excluded from primary analyses.Results. There were 600 RT-PCR-confirmed SARS-CoV-2 infections between May 1, 2020 and March 10, 2022 with ELISA data prior to infection. Prior infection was associated with 48% shorter shedding times, event time ratio (ETR) 0.52 (95% CI: 0.39-0.69, mean shedding: 13.7 vs 26.4 days). A 4-fold higher anti-SARS-CoV-2 spike titer was associated with 17% shorter shedding (ETR 0.83, 95% CI: 0.78-0.90). Similarly, maximum viral loads (lowest CT) were lower for previously infected individuals (mean CT 29.8 vs 28.0, p = 4.02x10-3). Shedding was shorter in previously infected adults and children [≥]10 years, but not in children 0-9 years; there was little difference in CT levels for previously infected vs naive adults above age 60.Conclusions. Prior infection-induced immunity was associated with shorter viral shedding and lower viral loads.Funding: This work was supported by the National Institute for Allergy and Infectious Diseases at the National Institute of Health [award no. R01 AI120997 to A.G., and contract nos. HHSN272201400006C and 75N93021C00016 to A.G.], and a grant from Open Philanthropy.

Burden of SARS-CoV-2 and protection from symptomatic second infection in children (preprint)

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.

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

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.

An immune correlate of SARS-CoV-2 infection and severity of reinfections (preprint)

Background. An immune correlate of protection from SARS-CoV-2 infection is urgently needed. Methods. We used an ongoing household cohort with an embedded transmission study that closely monitors participants regardless of symptom status. Real-time reverse-transcription polymerase chain reaction (RT-PCR) and Enzyme-linked immunosorbent assays (ELISAs) were used to measure infections and seropositivity. Sequencing was performed to determine circulating strains of SARS-CoV-2. We investigated the protection associated with seropositivity resulting from prior infection, the anti-spike antibody titers needed for protection, and we compared the severity of first and second infections. Results. In March 2021, 62.3% of the cohort was seropositive. After March 2021, gamma and delta variants predominated. Seropositivity was associated with 69.2% protection from any infection (95% CI: 60.7%-75.9%), with higher protection against moderate or severe infection (79.4%, 95% CI: 64.9%-87.9%). Anti-spike titers of 327 and 2,551 were associated with 50% and 80% protection from any infection; titers of 284 and 656 were sufficient for protection against moderate or severe disease. Second infections were less severe than first infections (Relative Risk (RR) of moderated or severe disease: 0.6, 95% CI: 0.38-0.98; RR of subclinical disease:1.9, 95% CI: 1.33-2.73). Conclusions. Prior infection-induced immunity is protective against infection when predominantly gamma and delta SARS-CoV-2 circulated. The protective antibody titers presented may be useful for vaccine policy and control measures. While second infections were somewhat less severe, they were not as mild as ideal. A strategy involving vaccination will be needed to ease the burden of the SARS-CoV-2 pandemic.

Epidemics of chikungunya, Zika, and COVID-19 reveal bias in case-based mapping (preprint)

ABSTRACT Accurate tracing of epidemic spread over space enables effective control measures. We examined three metrics of infection and disease in a pediatric cohort (N ≈ 3,000) over two chikungunya and one Zika epidemic, and in a household cohort (N=1,793) over one COVID-19 epidemic in Managua, Nicaragua. We compared spatial incidence rates (cases/total population), infection risks (infections/total population), and disease risks (cases/infected population). We used generalized additive and mixed-effects models, Kulldorf’s spatial scan statistic, and intracluster correlation coefficients. Across different analyses and all epidemics, incidence rates considerably underestimated infection and disease risks, producing large and spatially non-uniform biases distinct from biases due to incomplete case ascertainment. Infection and disease risks exhibited distinct spatial patterns, and incidence clusters inconsistently identified areas of either risk. While incidence rates are commonly used to infer infection and disease risk in a population, we find that this can induce substantial biases and adversely impact policies to control epidemics. Article summary line Inferring measures of spatial risk from case-only data can substantially bias estimates, thereby weakening and potentially misdirecting measures needed to control an epidemic.