Researchers of several long-term studies are uncovering the groundwork for more effective flu prevention strategies, as well as a potential universal vaccine that would replace annual flu vaccinations. In an international collaborative effort studying various cohorts, researchers are using the data and samples to track interactions between the flu virus and the body’s immune system response. Learn more about the global DIVINCI study and its corresponding cohort studies from around the world.

Worldwide

DIVINCI: Dissection of Influenza Vaccination and Infection for Childhood Immunity

DIVINCI is a collaborative endeavor of an international consortium made up of 15 investigators from 12 different institutions. Co-led by Paul Thomas, PhD, of St. Jude Children’s Research Hospital, and Aubree Gordon, PhD, of the University of Michigan, the consortium’s overarching goal is to understand the complex interaction between infection and immunity, specifically within the context of the influenza virus. To accomplish this important work, the consortium is leveraging data and samples obtained from previous influenza cohorts:

• FLU09 Cohort in Memphis, Tennessee
• HICS in Managua, Nicaragua
• NPICS in Managua, Nicaragua

The consortium is also establishing and conducting additional birth influenza cohorts across the globe:

• NPICS in Managua, Nicaragua
• WellKiwis in Wellington, New Zealand
• LA Cohort in Los Angeles, California

Read about about DIVINCI at stjude.org and pialab.org.

• Long-term studies will track indelible marks of first flu in Nature, 2019.
• NIH announces two awards for multi-year studies of influenza immunity in children from NIH, 2019.

Participating Institutions:

• St. Jude Children’s Research Hospital
• University of Michigan
• Institute of Environmental Science and Research
• Children’s Hospital of Los Angeles
• University of Chicago
• Stanford University
• Icahn School of Medicine at Mount Sinai
• Washington University in St. Louis
• University of Washington at Madison
• Emory University
• University of Rochester
• University of Melbourne, Peter Doherty Institute

Selection of Cohort Sites

Northern Hemisphere, Tropical, and Southern Hemisphere sites: year round influenza transmission

WellKiwis

• New Zealand
• Extensive experience conducting influenza studies
• Low loss to follow-up and highly compliant population
• Moderate vaccination rates
• Single-vaccination record

Los Angeles

• Experience conducting maternal-infant studies
• High rates of vaccination

Nicaragua Pediatric Influenza Cohort

• Extensive experience conducting pediatric influenza studies
• Low loss to follow-up
• Birth cohort ongoing for eight years
• Low to moderate rates of vaccination
• Single vaccination source

LOS ANGELES, CALIFORNIA, UNITED STATES

LA Cohort

The LA Cohort, a pregnancy and birth cohort that is being established as part of DIVINCI, will enroll a total of 150 infants per year for three years. Follow up will last for seven years. Pregnant women will be enrolled prior to the infant’s birth and breast-feeding women will be enrolled at the time of infant enrollment.

The cohort is being conducted at the Children’s Hospital Los Angeles (CHLA) and its surrounding hospitals and community. CHLA provides care to a large and highly diverse pediatric population. The CHLA General Pediatric Clinic sees 75-100 newborns each month. In addition, recruitment will occur at Hollywood Presbyterian Medical Center (HPMC), located next door to CHLA where over 5000 mothers deliver their babies each year. This hospital serves a low-income, culturally diverse population. Kaiser Permanente, also adjacent to CHLA, serves as a third recruitment site for our healthy mother-infant studies. Kaiser delivers over 1000 babies per year and serves a middle-income population. Previous studies enrolled approximately 60% Hispanic, 25% White, 5% African- American, 5% Asian, and 5% other, which reflects the population using the services at the enrollment sites.

Given a sample size of 450 infants enrolled continuously over the first three years, a vaccination rate of 50%, and a withdrawal rate of 5% per year applying the rates of influenza documented in the Nicaraguan Pediatric Influenza Cohort Study for unvaccinated children and half of the rate for unvaccinated children, we expect to detect 323 RT-PCR influenza cases and 611 influenza infections. In addition, we expect to have a total of 1068 samples following vaccination over the seven-year time period, including 207 samples from naïve children whose first influenza exposure is influenza vaccine. This sample size combined with the other two cohort studies will give us > 80% (in most cases > 95% power) for the main immunological comparisons we propose to make.

Enrollment will be limited to infants under 2 months of age and their mothers. Children will eligible until 18 years of age, pending continued funding. There are no sex limitations.

The initial enrollment began in April 2019.

Managua, Nicaragua

NPICS: The Nicaraguan Pediatric Influenza Cohort Study

NPICS, which began in January 2011, is a community-based prospective study of children aged 0 months to 14 years in Managua, Nicaragua. The study is unique because, unlike other influenza studies, many participants have been followed year-round since birth. The study aims to characterize the burden and seasonality of influenza in Nicaraguan children, to examine risk factors for influenza virus infection and disease severity, and to investigate sequential influenza virus infections. As of 2018, 2,767 infants and children have participated in the cohort since its inception, with 1,768 current active participants (49.6% male). Average participation time in the cohort is 4.2 years (range 0-7) and loss-to-follow-up is low, with 73% of eligible children participating the entire time. In addition, of 1,057 children who were enrolled from birth, 856 (81%) are still active participants. These 856 children have 4,565 banked blood samples and 6,975 banked respiratory samples and experienced a total of 897 RT-PCR-positive influenza episodes.

Since January 2011, we have detected a total of 1,594 RT-PCR-positive influenza episodes. Whole-genome sequence of infecting influenza viruses is available from about 600 cohort influenza cases. Respiratory samples are available for all cases should additional sequencing be needed. The overall rate of RT-PCR-positive, symptomatic influenza infection was 14.2 cases per 100 person-years (py) (95% CI: 13.6, 15.0). Incidence varies with age, with the highest incidence observed in children under 2 years of age (IR: 20.9 cases per 100 py, 95% CI: 18.7, 23.3). By the age of 2, more than 50% of children experienced at least one clinical RT-PCR-positive influenza infection. Importantly, serology on a random subset of infants and toddlers indicates that we have captured 88% of first influenza A infections by RT-PCR (serology not yet available for influenza B).

The Nicaraguan Pediatric Influenza Cohort will continue as part of DIVINCI.

Wellington, New Zealand

WellKiwis

WellKiwis is a birth cohort study of children aged 0 to 7 years in Wellington, New Zealand that was established as part of DIVINCI.

The source population is the Wellington region, where the age, ethnicity and socioeconomic distribution are broadly similar to the New Zealand population: 73% European, 12% Maori, 10% Asian and 8% Pacific peoples. About 6,000 live births occur in the Wellington region each year.

We plan to recruit a total of 600 infants (200 infants per year during the first three years). Assuming a retention rate of 90%, we would retain 540 participants. Based on the 2015 SHIVERS serosurvey, young children had about 20% vaccination rate, about 36% of HAI or NAI seroconversion and 13-17% influenza PCR-positive rate depending on age. Of the 600 participants, 120 will be vaccinated and 480 unvaccinated. Over the course of the study, we estimate that we will have a 10% withdrawal rate. We estimate that over the seven years we will have 506 influenza cases and 1,215 influenza infections. This sample size combined with the other two cohort studies will give us greater than 80% (in most cases >95% power) for the main immunological comparisons we propose to make.

Participants will be limited to newborns and children, including both sexes residing in the Wellington region. Enrollment will be limited to infants aged no more than four weeks.

Initial enrolment began October 2019 with the cohort year defined from October 1 to September 30 of the following year. Infants will be enrolled in the first three study years. Enrolled children will be followed until the end of the study period (March 2026), they are lost to follow-up or they withdraw from the study.

In years 4-7, the three birth cohorts recruited in years 1-3 will be followed with the same influenza season surveillance and blood and respiratory swab collection schedule used for follow-up years, with post-season blood serving as baseline for the subsequent season.

Memphis, Tennessee, United States

FLU09 Cohort

FLU09 was established in Memphis as a collaboration between St. Jude Children’s Research Hospital, Le Bonheur Children’s Hospital, and the University of Tennessee Health Sciences Center to recruit a cohort of naturally acquired influenza infection patients in response to the 2009 influenza pandemic. The goal of this study was to identify associations between viral loads, disease severity/outcome, and the acute and memory immune responses. FLU09 was a five-year prospective, longitudinal study that ran from Fall 2009 to Spring 2014. Pediatric influenza cases were enrolled as index cases while household members were enrolled when possible. Samples were collected at Days 0 (enrollment), 3, 7, 10, and 28 when possible. Clinical information was collected, including symptoms, over the course of influenza infection. In total, 383 individuals were enrolled with 166 individuals who were infected with influenza.

Managua, Nicaragua

HICS: The Household Influenza Cohort Study

The Household Influenza Cohort Study is an R01-funded study of influenza transmission in households in Managua. The study began in May 2017 and within six weeks had fully enrolled the cohort (2,209 individuals aged 0-92). In the first year, the study identified 350 influenza-positive episodes.

This cohort study involves collection of acute and convalescent samples surrounding influenza infection or influenza infection in one of the household members. We have been successful at collecting 96% of paired samples. Because blood samples are collected from all household members at the identification of an influenza case in the household, this study is able to identify and collect blood from individuals directly before exposure to influenza as well as to get paired samples around asymptomatic cases.