Test-negative Design Research Articles

Effectiveness and impact of monovalent rotavirus vaccination in Afghanistan: a test-negative case–control analysis

Afghanistan introduced monovalent rotavirus vaccine (Rotarix) into its national immunisation schedule in January, 2018. While post-licensure studies have shown substantial declines in rotavirus gastroenteritis cases and deaths globally, there is little evidence of rotavirus vaccine effectiveness and impact from low-income countries in Asia. We aimed to evaluate the effectiveness of the Rotarix vaccine and the impact of Rotarix vaccine on rotavirus gastroenteritis hospitalisations (ie, hospital admissions) among children younger than 5 years in Afghanistan. We used a test-negative case-control design embedded in an active sentinel surveillance platform to evaluate vaccine effectiveness. Children born on or after Jan 1, 2018, who had documentation of their rotavirus vaccination status and who were admitted for acute gastroenteritis at one of four sentinel hospitals from May, 2018 to December, 2021 were eligible to be included. We used an unconditional logistic regression model to estimate vaccine effectiveness and 95% CIs for a complete series of doses compared with no rotavirus vaccine doses among patients admitted with acute gastroenteritis. Vaccine effectiveness against hospitalisation was calculated as (1 - [odds of being vaccinated in cases] / [odds of being vaccinated in controls]) × 100%. We compared pre-vaccine (2013-15) and post-vaccine (2019-21) surveillance data from two sites to calculate vaccine impact. The vaccine effectiveness analysis included 1172 cases and 2173 controls. Approximately 2108 (63·0%) of 3345 cases and controls were male, 1237 (37·0%) were female, and 2171 (65·0%) were aged 6-11 months. Two doses of Rotarix were 45% (95% CI 22-62) effective against rotavirus hospitalisation in children aged 6-59 months, adjusting for age, severity, admission year, and rotavirus season. Rotavirus positivity decreased from 51% pre-vaccine to 39% post-vaccine, resulting in a 39% adjusted reduction in rotavirus positivity among children younger than 5 years admitted with acute gastroenteritis. Rotarix showed moderate effectiveness in preventing rotavirus gastroenteritis hospitalisations, consistent with findings in other low-income countries. These findings support the continued administration of the rotavirus vaccine in Afghanistan. Gavi, the Vaccine Alliance. For the Dari translation of the abstract see Supplementary Materials section.

Effectiveness of the Original Monovalent and Bivalent COVID-19 Vaccines Against COVID-19-Associated Emergency Department and Urgent Care Encounters in Pregnant Persons Who Were Not Immunocompromised: VISION Network, June 2022-August 2023.

Pregnant people face increased risk of severe COVID-19. Current guidelines recommend updated COVID-19 vaccination (2023-2024) for those aged ≥6 months, irrespective of pregnancy status. To refine recommendations for pregnant people, further data are needed. Using a test-negative design, we evaluated COVID-19 vaccine effectiveness against medically attended COVID-19 with COVID-19-like illness among pregnant people aged 18 to 45 years during June 2022 to August 2023. When doses were received during pregnancy, vaccine effectiveness was 52% (95% CI, 29%-67%); when received <6 months prior to pregnancy, 28% (95% CI, 11%-42%); and when received ≥6 months prior to pregnancy, 6% (95% CI, -11% to 21%). Pregnant people should stay up-to-date with recommended COVID-19 vaccination.

Effectiveness of inactivated influenza vaccine in children during the 2023/24 season: The first season after relaxation of intensive COVID-19 measures

BackgroundThe annual administration of the influenza vaccine is the most effective method for preventing influenza. We have evaluated the effectiveness of the inactivated influenza vaccine in children aged 6 months to 15 years across the seasons from 2013/2014 to 2022/2023. This study aims to investigate the effectiveness of the inactivated influenza vaccine in the 2023/2024 season, the first year following the easing of strict COVID-19 measures, and possibly the last season when only the inactivated vaccine is available on the market. MethodsAdjusted vaccine effectiveness for the 2023/2024 season was assessed using a test-negative case-control design, with results based on polymerase chain reaction and rapid influenza diagnostic tests. Vaccine effectiveness was calculated by influenza type and patient hospitalization/outpatient status. ResultsA total of 1832 children were recruited. The inactivated influenza vaccine was effective in preventing both symptomatic influenza A and B in both inpatient and outpatient settings. Overall vaccine effectiveness for influenza A was 51% (95% confidence interval [CI], 23%–69%, n = 930) in inpatient settings and 54% (95%CI, 27%–71%, n = 559) in outpatient settings. For influenza B, effectiveness was 60% (95%CI, 22%–79%, n = 859) in inpatient settings and 56% (95%CI, 26%–74%, n = 558) in outpatient settings. Analysis suggested that administering two doses enhanced effectiveness specifically against influenza B. ConclusionsThis is the first study to demonstrate influenza vaccine effectiveness in children after the relaxation of strict COVID-19 measures in Japan (2023/2024). We recommend the current inactivated vaccine for preventing both influenza A and B in children, with consideration for the potential use of two doses to enhance effectiveness against influenza B.

Evaluation of the COVID-19 vaccine effectiveness on the outcomes of COVID 19 disease in Iran: a test-negative case-control study.

This study measures the COVID-19 vaccine effectiveness (CVE) against hospital admission and severe COVID-19. This study is a test-negative case-control design using data from eight provinces in April, 2021 until March, 2022. The individuals were classified as cases and controls based on the results of the RT-PCR test for SARS-CoV-2 and matched based on the timing of the test being conducted as well as the timing of hospital admission. The measure of association was an odds ratio (OR) by univariate and multiple logistic regression. The multiple logistic regression has been carried out to take confounding factors and potential effect modifiers into account. The CVE was computed as CVE = (1 - OR)*100 with 95% confidence interval. Among 19314 admitted patients, of whom 13216 (68.4%) were cases and 6098 (31.6%) were controls, 1313 (6.8%) died. From total, 5959 (30.8%) patients had received the vaccine in which one, two, and booster doses were 2443 (12.6%), 2796 (14.5٪), and 720 (3.7٪), respectively. The estimated adjusted effectiveness of only one dose, two doses and booter vaccination were 22% (95% CI: 14%-29%), 35% (95% CI: 29%-41%) and 33% (95% CI: 16%-47%), respectively. In addition, the adjusted vaccine effectiveness against severe outcome was 33% (95% CI: 19%- 44%), 34% (95% CI: 20%- 45%) and 20% (95% CI: -29%- 50%) for those who received one, two and booster vaccinations, respectively. Our study concluded that full vaccination, though less effective compared to similar studies elsewhere, decreased hospital admissions and deaths from COVID-19 in Iran, particularly during the Delta variant period, with an observed decline during the Omicron variant dominance.

Potential Biases in Test-Negative Design Studies of COVID-19 Vaccine Effectiveness Arising from the Inclusion of Asymptomatic Individuals.

The test-negative design (TND) is a popular method for evaluating vaccine effectiveness (VE). A "classical" TND study includes symptomatic individuals tested for the disease targeted by the vaccine to estimate VE against symptomatic infection. However, recent applications of the TND have attempted to estimate VE against infection by including all tested individuals, regardless of their symptoms. In this article, we use directed acyclic graphs and simulations to investigate potential biases in TND studies of COVID-19 VE arising from the use of this "alternative" approach, particularly when applied during periods of widespread testing. We show that the inclusion of asymptomatic individuals can potentially lead to collider stratification bias, uncontrolled confounding by health and healthcare-seeking behaviors (HSBs), and differential outcome misclassification. While our focus is on the COVID-19 setting, the issues discussed here may also be relevant in the context of other infectious diseases. This may be particularly true in scenarios where there is either a high baseline prevalence of infection, a strong correlation between HSBs and vaccination, different testing practices for vaccinated and unvaccinated individuals, or settings where both the vaccine under study attenuates symptoms of infection and diagnostic accuracy is modified by the presence of symptoms.

Caveats Regarding the Test-Negative Design to Study Mpox (monkeypox) Risk Factors and Vaccine Effectiveness.

The test-negative design (TND) has been commonly used to study vaccine effectiveness (notably regarding COVID-19 and influenza vaccines) and has been recently proposed as a valid design to study causal risk factors of diseases during an outbreak. In April 2022, mpox (previously monkeypox) led to a worldwide outbreak that resulted in an international public health emergency. The TND could be used to study vaccine effectiveness and risk factors of mpox using epidemiologic databases, and a few studies have already done so. However, several issues prevent such study design from being valid for this end. Problems stem from stigma surrounding mpox, which impacts a person's decision to look for healthcare. This poses a challenge to the "similar healthcare seeking behaviour" assumption that is central for test negative studies. Further limitations include the differential diagnoses of mpox, which have notable differences from mpox that may be easily detected by clinicians or patients but are unlikely to be included in epidemiologic databases or electronic health records. Herein I discuss caveats regarding the use of the TND in the context of the mpox outbreak, as well as potential steps that may allow it to be used effectively.

COVID-19 Vaccine Effectiveness Studies against Symptomatic and Severe Outcomes during the Omicron Period in Four Countries in the Eastern Mediterranean Region.

Vaccine effectiveness (VE) studies provide real-world evidence to monitor vaccine performance and inform policy. The WHO Regional Office for the Eastern Mediterranean supported a regional study to assess the VE of COVID-19 vaccines against different clinical outcomes in four countries between June 2021 and August 2023. Health worker cohort studies were conducted in 2707 health workers in Egypt and Pakistan, of whom 171 experienced symptomatic laboratory-confirmed SARS-CoV-2 infection. Test-negative design case-control studies were conducted in Iran and Jordan in 4017 severe acute respiratory infection (SARI) patients (2347 controls and 1670 cases) during the Omicron variant dominant period. VE estimates were calculated for each study and pooled by study design for several vaccine types (BBIBP-CorV, AZD1222, BNT162b2, and mRNA-1273, among others). Among health workers, VE against symptomatic infection of a complete primary series could only be computed compared to partial vaccination, suggesting a benefit of providing an additional dose of mRNA vaccines (VE: 88.9%, 95%CI: 15.3-98.6%), while results were inconclusive for other vaccine products. Among SARI patients, VE against hospitalization of a complete primary series with any vaccine compared to non-vaccinated was 20.9% (95%CI: 4.5-34.5%). Effectiveness estimates for individual vaccines, booster doses, and secondary outcomes (intensive care unit admission and death) were inconclusive. Future VE studies will need to address challenges in both design and analysis when conducted late during a pandemic and will be able to utilize the strengthened capacities in countries.

Real-world effectiveness of original BNT162b2 mRNA COVID-19 against symptomatic Omicron infection among children 5–11 years of age in Brazil: A prospective test-negative design study

ObjectiveTo estimate original wild-type BNT162b2 effectiveness against symptomatic Omicron infection among children 5–11 years of age. MethodsThis prospective test-negative, case-control study was conducted in Toledo, southern Brazil, from June 2022 to July 2023. Patients were included if they were aged 5–11 years, sought care for acute respiratory symptoms in the public health system, and were tested for SARS-CoV-2 using reverse transcription polymerase chain reaction. In the primary analysis, we determined the effectiveness of two doses of original wild-type BNT162b2 against symptomatic COVID-19. The reference exposure group was the unvaccinated. ResultsA total of 757 children were enrolled; of these, 461 (25 cases; 436 controls) were included in the primary analysis. Mean age was 7.4 years, 49.7 % were female, 34.6 % were obese, and 14.1 % had chronic pulmonary disease. Omicron accounted for 100 % of all identified SARS-CoV-2 variants with BA.5, BQ.1, and XBB.1 accounting for 35.7 %, 21.4 % and 21.4 %, respectively. The adjusted estimate of two-dose vaccine effectiveness against symptomatic Omicron was 3.1 % (95 % CI, -133.7 % to 61.8 %) after a median time between the second dose and the beginning of COVID-19 symptoms of 192.5 days (interquartile range, 99 to 242 days). ConclusionIn this study with children 5–11 years of age, a two dose-schedule of original wild-type BNT162b2 was not associated with a significant protection against symptomatic Omicron infection after a median time between the second dose and the beginning of COVID-19 symptoms of 192 days, although the study may have been underpowered to detect a clinically important difference. Trial registration numberClinicalTrials.gov number, NCT05403307 (https://classic.clinicaltrials.gov/ct2/show/NCT05403307)

Hypothesis testing and sample size considerations for the test-negative design

The test-negative design (TND) is an observational study design to evaluate vaccine effectiveness (VE) that enrolls individuals receiving diagnostic testing for a target disease as part of routine care. VE is estimated as one minus the adjusted odds ratio of testing positive versus negative comparing vaccinated and unvaccinated patients. Although the TND is related to case–control studies, it is distinct in that the ratio of test-positive cases to test-negative controls is not typically pre-specified. For both types of studies, sparse cells are common when vaccines are highly effective. We consider the implications of these features on power for the TND. We use simulation studies to explore three hypothesis-testing procedures and associated sample size calculations for case–control and TND studies. These tests, all based on a simple logistic regression model, are a standard Wald test, a continuity-corrected Wald test, and a score test. The Wald test performs poorly in both case–control and TND when VE is high because the number of vaccinated test-positive cases can be low or zero. Continuity corrections help to stabilize the variance but induce bias. We observe superior performance with the score test as the variance is pooled under the null hypothesis of no group differences. We recommend using a score-based approach to design and analyze both case–control and TND. We propose a modification to the TND score sample size to account for additional variability in the ratio of controls over cases. This work enhances our understanding of the data generating mechanism in a test-negative design (TND) and how it is distinct from that of a case-control study due to its passive recruitment of controls.

Relative vaccine effectiveness of MF59-adjuvanted vs high-dose trivalent inactivated influenza vaccines for prevention of test-confirmed influenza hospitalizations during the 2017–2020 influenza seasons

ObjectivesThis study evaluated relative vaccine effectiveness (rVE) of MF59-adjuvanted trivalent inactivated influenza vaccine (aTIV) vs high-dose trivalent inactivated influenza vaccine (HD-TIV) for prevention of test-confirmed influenza emergency department visits and/or inpatient admissions (“ED/IP”) and for IP admissions alone pooled across the 2017–2020 influenza seasons. Exploratory individual season analyses were also performed. MethodsThis retrospective test-negative design study included United States (US) adults age ≥65 years vaccinated with aTIV or HD-TIV who presented to an ED or IP setting with acute respiratory or febrile illness during the 2017–2020 influenza seasons. Test-positive cases and test-negative controls were grouped by vaccine received. The rVE of aTIV vs HD-TIV was evaluated using a combination of inverse probability of treatment weighting and logistic regression to adjust for potential confounders. ResultsPooled analyses over the three seasons found no significant differences in the rVE of aTIV vs HD-TIV for prevention of test-confirmed influenza ED/IP (−2.5% [−19.6, 12.2]) visits and admissions or IP admissions alone (−1.6% [−22.5, 15.7]). The exploratory individual season analyses also showed no significant differences. ConclusionsEvidence from the 2017–2020 influenza seasons indicates aTIV and HD-TIV are comparable for prevention of test-confirmed influenza ED/IP visits in US adults age ≥65 years.

Influenza virus circulation and vaccine effectiveness during June 2021–May 2023 in Thailand

Thai Ministry of Public Health recommends influenza vaccination for certain risk groups. We evaluated 2023 Southern Hemisphere influenza vaccine effectiveness against medically attended influenza using surveillance data from nine Thai hospitals and a test-negative design. During June 2022–May 2023, influenza vaccine provided moderate protection against seeking care for influenza illness (adjusted vaccine effectiveness 51%; 95% confidence interval 28–67). Understanding vaccine effectiveness can help guide future antigen selection and support clinicians to make a strong influenza vaccine recommendation to patients.

Prior infections and effectiveness of SARS-CoV-2 vaccine in test-negative studies: A systematic review and meta-analysis.

Prior infection with SARS-CoV-2 can provide protection against infection and severe COVID-19. We aimed to determine the impact of pre-existing immunity on the vaccine effectiveness (VE) estimates. We systematically reviewed and meta-analysed 66 test-negative design (TND) studies that examined VE against infection or severe disease (hospitalization, ICU admission, or death) for primary vaccination series. Pooled VE among studies that included people with prior COVID-19 infection was lower against infection (pooled VE: 77%; 95% confidence interval (CI): 72%, 81%) and severe disease (pooled VE: 86%; 95% CI: 83%, 89%), compared with studies that excluded people with prior COVID-19 infection (pooled VE against infection: 87%; 95% CI: 85%, 89%; pooled VE against severe disease: 93%; 95% CI: 91%, 95%). There was a negative correlation between VE estimates against infection and severe disease, and the cumulative incidence of cases before the start of the study or incidence rates during the study period. We found clear empirical evidence that higher levels of pre-existing immunity were associated with lower VE estimates. Prior infections should be treated as both a confounder and effect modificatory when the policies target the whole population or stratified by infection history, respectively.

Leveraging a clinical emergency department dataset to estimate two-dose COVID-19 vaccine effectiveness and duration of protection in Canada

BackgroundDuring the COVID-19 pandemic, clinical care shifted toward virtual and Emergency Department care. We explored the feasibility of mRNA vaccine effectiveness (VE) estimation against SARS-CoV-2-related Emergency Department visits and hospitalizations using prospectively collected Emergency Department data. MethodsWe estimated two-dose VE using a test-negative design and data from 10 participating sites of the Canadian COVID-19 Emergency Department Rapid Response Network (CCEDRRN). We included Emergency Department patients presenting with COVID-19 symptoms and nucleic acid amplification testing for SARS-CoV-2 between July 19 and December 31, 2021. We excluded patients with unclear vaccination and one or more than 2 vaccine doses by their Emergency Department visit. ResultsAmong 3,405 eligible patients, adjusted two-dose mRNA VE against SARS-CoV-2-related Emergency Department visits was 93.3 % (95 % CI 87.9–96.3 %) between 7–55 days, sustained over 80 % through 139 days post-vaccination. In stratified analyses, VE was similar among patients with select immune-compromising conditions, chronic kidney disease, lung disease, unstable housing, and reported illicit substance use. ConclusionsTwo-dose mRNA VE against SARS-CoV-2-related Emergency Department visit was high and sustained, including among vulnerable subgroups. Compared to administrative datasets, active Emergency Department enrolment enables standardization for testing access and indication and supports separate VE assessment among special population subgroups. Compared to other active enrolment settings, Emergency Departments more consistently function during crises when alternate healthcare sectors become variably closed.Trial registration: Clinicaltrials.gov, NCT0470294.

Evaluation of pre-exposure vaccine effectiveness against mpox during the 2022–2023 mpox outbreak in the Madrid region (Spain): a test-negative design

IntroductionAn appropriate vaccination approach is critical to control the current outbreak of mpox but there is little research providing information on its effectiveness, particularly under circumstances of limited vaccine availability.MethodsPre-exposure...

Effect of Non-Rotavirus Enteric Infections on Vaccine Efficacy in a ROTASIIL Clinical Trial.

This study examined the relative proportion of enteric pathogens associated with severe gastroenteritis (GE) among children younger than 2 years in a phase III efficacy trial of the ROTASIIL® vaccine in India, evaluated the impact of co-infections on vaccine efficacy (VE), and characterized the association between specific pathogens and the clinical profile of severe GE. Stored stool samples collected from cases of severe GE in the phase III trial were tested by quantitative polymerase chain reaction using TaqMan™ Array Cards. Etiology was attributed by calculating the adjusted attributable fraction (AF) for each pathogen. A test-negative design was used to estimate VE. The pathogens with the highest AFs for severe diarrhea were rotavirus (23.5%), adenovirus 40/41 (17.0%), Shigella spp./enteroinvasive Escherichia coli, norovirus GII, enterotoxigenic E. coli, and Cryptosporidium spp. A considerable proportion of the disease in these children could not be explained by the pathogens tested. Severe GE cases associated with rotavirus and Shigella spp. were more likely to have a longer duration of vomiting and diarrhea, respectively. Cases attributed to Cryptosporidium spp. were more severe and required hospitalization. In the intention-to-treat population, VE was estimated to be 43.9% before and 46.5% after adjustment for co-infections; in the per-protocol population, VE was 46.7% before and 49.1% after adjustments. Rotavirus continued to be the leading cause of severe GE in this age group. The adjusted VE estimates obtained did not support co-infections as a major cause of lower vaccine performance in low- and middle-income countries.

Effectiveness of COVID-19 vaccines administered in the 2023 autumnal campaigns in Europe: Results from the VEBIS primary care test-negative design study, September 2023–January 2024

In autumn 2023, European vaccination campaigns predominantly administered XBB.1.5 vaccine. In a European multicentre study, we estimated 2023 COVID-19 vaccine effectiveness (VE) against laboratory-confirmed symptomatic infection at primary care level between September 2023 and January 2024. Using a test-negative case–control design, we estimated VE in the target group for COVID-19 vaccination overall and by time since vaccination. We included 1057 cases and 4397 controls. Vaccine effectiveness was 40 % (95 % CI: 26–53 %) overall, 48 % (95 % CI: 31–61 %) among those vaccinated < 6 weeks of onset and 29 % (95 % CI: 3–49 %) at 6–14 weeks. Our results suggest that COVID-19 vaccines administered to target groups during the autumn 2023 campaigns showed clinically significant effectiveness against laboratory-confirmed, medically attended symptomatic SARS-CoV-2 infection in the 3 months following vaccination. A longer study period will allow for further variant-specific COVID-19 VE estimates, better understanding decline in VE and informing booster administration policies.

Late-Season Influenza Vaccine Effectiveness Against Medically Attended Outpatient Illness, United States, December 2022-April 2023.

The 2022-23 US influenza season peaked early in fall 2022. Late-season influenza vaccine effectiveness (VE) against outpatient, laboratory-confirmed influenza was calculated among participants of the US Influenza VE Network using a test-negative design. Of 2561 participants enrolled from December 12, 2022 to April 30, 2023, 91 laboratory-confirmed influenza cases primarily had A(H1N1)pdm09 (6B.1A.5a.2a.1) or A(H3N2) (3C.2a1b.2a.2b). Overall, VE was 30% (95% confidence interval -9%, 54%); low late-season activity precluded estimation for most subgroups. 2022-23 late-season outpatient influenza VE was not statistically significant. Genomic characterization may improve the identification of influenza viruses that circulate postinfluenza peak.

Nirsevimab Effectiveness Against Cases of Respiratory Syncytial Virus Bronchiolitis Hospitalised in Paediatric Intensive Care Units in France, September 2023-January 2024.

In September 2023, France was one of the first countries that started a national immunisation campaign with nirsevimab, a new monoclonal antibody against respiratory syncytial virus (RSV). Using data from a network of paediatric intensive care units (PICUs), we aimed to estimate nirsevimab effectiveness against severe cases of RSV bronchiolitis in France. We conducted a case-control study based on the test-negative design and included 288 infants reported by 20 PICUs. We estimated nirsevimab effectiveness at 75.9% (48.5-88.7) in the main analysis and 80.6% (61.6-90.3) and 80.4% (61.7-89.9) in two sensitivity analyses. These real-world estimates confirmed the efficacy observed in clinical studies.

Varicella-Zoster Virus-Induced Neurologic Disease After COVID-19 Vaccination: A Multicenter Observational Cohort Study.

Early reports described an increased risk of herpes zoster following receipt of mRNA-based COVID-19 vaccines. The objective was to assess whether COVID-19 vaccine is associated with varicella-zoster virus-induced neurologic disease (VZV-ND). This multicenter retrospective case-control study with a test-negative design was conducted at 12 hospitals in Israel. We included all patients admitted with VZV-ND between January 2020 and December 2021 and matched controls with a negative polymerase chain reaction result for VZV in cerebrospinal fluid. We identified 188 patients meeting the case definition of VZV-ND who were admitted during the study period. Cases were matched with 376 controls. There was no significant variation in the incidence of VZV-ND between 1 year preceding and 1 year following the deployment of BNT162b2 in Israel. Analysis of persons who had received at least 1 dose of COVID-19 vaccine (n = 259) showed similar proportions of VZV-ND and non-VZV-ND in 4 intervals (30, 42, 50, 60 days) following the last vaccine dose. The median time from the last vaccine dose to hospitalization with a neurologic syndrome was 53 days (IQR, 25-128) and 82 days (IQR, 36-132) for VZV-ND and non-VZV-ND, respectively, not reaching statistical significance (P = .056). The rate of VZV-ND in vaccinated patients was no different from the rate in the unvaccinated group (30.9% vs 35.4%, P = .2). We did not find an association between COVID-19 vaccine and VZV-ND. Since COVID-19 vaccine is now recommended yearly, every fall and winter, establishing the safety of the vaccine is of great importance.

Mixed methods approach to examining the implementation experience of a phone-based survey for a SARS-CoV-2 test-negative case-control study in California.

To describe the implementation of a test-negative design case-control study in California during the Coronavirus Disease 2019 (COVID-19) pandemic. Test-negative case-control study. Between February 24, 2021 - February 24, 2022, a team of 34 interviewers called 38,470 Californians, enrolling 1,885 that tested positive for SARS-CoV-2 (cases) and 1,871 testing negative for SARS-CoV-2 (controls) for 20-minute telephone survey. We estimated adjusted odds ratios for answering the phone and consenting to participate using mixed effects logistic regression. We used a web-based anonymous survey to compile interviewer experiences. Cases had 1.29-fold (95% CI: 1.24-1.35) higher adjusted odds of answering the phone and 1.69-fold (1.56-1.83) higher adjusted odds of consenting to participate compared to controls. Calls placed from 4pm to 6pm had the highest adjusted odds of being answered. Some interviewers experienced mental wellness challenges interacting with participants with physical (e.g., food, shelter, etc.) and emotional (e.g., grief counseling) needs, and enduring verbal harassment from individuals called. Calls placed during afternoon hours may optimize response rate when enrolling controls to a case-control study during a public health emergency response. Proactive check-ins and continual collection of interviewer experience(s) and may help maintain mental wellbeing of investigation workforce. Remaining adaptive to the dynamic needs of the investigation team is critical to a successful study, especially in emergent public health crises, like that represented by the COVID-19 pandemic.