The Use of Test-negative Controls to Monitor Vaccine Effectiveness: A Systematic Review of Methodology.

BACKGROUND: The test-negative design is an increasingly popular approach for estimating vaccine effectiveness (VE) due to its efficiency. This review aims to examine published test-negative design studies of VE and to explore similarities and differences in methodological choices for different diseases and vaccines. METHODS: We conducted a systematic search on PubMed, Web of Science, and Medline, for studies reporting the effectiveness of any vaccines using a test-negative design. We screened titles and abstracts and reviewed full texts to identify relevant articles. We created a standardized form for each included article to extract information on the pathogen of interest, vaccine(s) being evaluated, study setting, clinical case definition, choices of cases and controls, and statistical approaches used to estimate VE. RESULTS: We identified a total of 348 articles, including studies on VE against influenza virus (n = 253), rotavirus (n = 48), pneumococcus (n = 24), and nine other pathogens. Clinical case definitions used to enroll patients were similar by pathogens of interest but the sets of symptoms that defined them varied substantially. Controls could be those testing negative for the pathogen of interest, those testing positive for nonvaccine type of the pathogen of interest, or a subset of those testing positive for alternative pathogens. Most studies controlled for age, calendar time, and comorbidities. CONCLUSIONS: Our review highlights similarities and differences in the application of the test-negative design that deserve further examination. If vaccination reduces disease severity in breakthrough infections, particular care must be taken in interpreting vaccine effectiveness estimates from test-negative design studies.

Effectiveness of Partial and Full Influenza Vaccination Among Children Aged <9 Years in Hong Kong, 2011-2019.

BACKGROUND: Two doses of influenza vaccination are recommended for previously unvaccinated children aged <9 years, and receipt of 1 dose is sometimes termed "partial vaccination." We assessed the effectiveness of partial and full influenza vaccination in preventing influenza-associated hospitalization among children in Hong Kong. METHODS: Using the test-negative design we enrolled 23 187 children aged <9 years admitted to hospitals with acute respiratory illness from September 2011 through March 2019. Vaccination and influenza status were recorded. Fully vaccinated children included those vaccinated with 2 doses or, if previously vaccinated, those vaccinated with 1 dose. Partially vaccinated children included those who should have received 2 doses but only received 1 dose. We estimated vaccine effectiveness (VE) by using conditional logistic regression models matched on epidemiological week. RESULTS: Overall VE estimates among fully and partially vaccinated children were 73% (95% confidence interval, 69%-77%) and 31% (95% confidence interval, 8%-48%), respectively. A consistently higher VE was observed in children fully vaccinated against each influenza virus type/subtype. The effectiveness of partial vaccination did not vary by age group. CONCLUSIONS: Partial vaccination was significantly less effective than full vaccination. Our study supports the current recommendation of 2 doses of influenza vaccination in previously unvaccinated children <9 years of age.

Early season estimate of influenza vaccination effectiveness against influenza hospitalisation in children, Hong Kong, winter influenza season 2018/19.

The winter 2018/19 influenza season in Hong Kong has been predominated by influenza A(H1N1)pdm09 as at January 2019. We enrolled 2,016 children in three public hospitals in Hong Kong between 2 September 2018 and 11 January 2019. Using the test-negative approach, we estimated high early season effectiveness of inactivated influenza vaccine against influenza A or B of 90% (95% confidence interval (CI): 80-95%) and 92% (95% CI: 82-96%) against influenza A(H1N1)pdm09.

Population seroprevalence of antibody to influenza A(H7N9) virus, Guangzhou, China.

BACKGROUND: Since the identification in early 2013 of severe disease caused by influenza A(H7N9) virus infection, there have been few attempts to characterize the full severity profile of human infections. Our objective was to estimate the number and severity of H7N9 infections in Guangzhou, using a serological study. METHODS: We collected residual sera from patients of all ages admitted to a hospital in the city of Guangzhou in southern China in 2013 and 2014. We screened the sera using a haemagglutination inhibition assay against a pseudovirus containing the H7 and N9 of A/Anhui/1/2013(H7N9), and samples with a screening titer ≥10 were further tested by standard hemagglutination-inhibition and virus neutralization assays for influenza A(H7N9). We used a statistical model to interpret the information on antibody titers in the residual sera, assuming that the residual sera provided a representative picture of A(H7N9) infections in the general population, accounting for potential cross-reactions. RESULTS: We collected a total of 5360 residual sera from December 2013 to April 2014 and from October 2014 to December 2014, and found two specimens that tested positive for H7N9 antibody at haemagglutination inhibition titer ≥40 and a neutralization titer ≥40. Based on this, we estimated that 64,000 (95 % credibility interval: 7300, 190,000) human infections with influenza A(H7N9) virus occurred in Guangzhou in early 2014, with an infection-fatality risk of 3.6 deaths (95 % credibility interval: 0.47, 15) per 10,000 infections. CONCLUSIONS: Our study suggested that the number of influenza A(H7N9) virus infections in Guangzhou substantially exceeded the number of laboratory-confirmed cases there, albeit with considerable imprecision. Our study was limited by the small number of positive specimens identified, and larger serologic studies would be valuable. Our analytic framework would be useful if larger serologic studies are done.

Influenza vaccine effectiveness against influenza-associated hospitalization in children in Hong Kong, 2010-2020.

BACKGROUND: Influenza virus infections can cause hospitalizations in children, and annual vaccination of children can provide protection against influenza. METHODS: We analyzed a test-negative design study with data spanning from 2010/11 through 2019/20 to evaluate influenza vaccine effectiveness (VE) against influenza hospitalization in children by age group, influenza type/subtype and time period within each season. We enrolled children admitted to hospital with acute febrile respiratory illnesses. Nasopharyngeal aspirates were tested by culture and/or RT-PCR to determine influenza status, and vaccination status was obtained by interviewing parents or legal guardians and was verified where possible. VE was estimated by conditional logistic regression model adjusting for sex, age and age-squared, matching on week. RESULTS: Influenza seasons in Hong Kong are prolonged with influenza-associated hospitalizations occurring in almost every month of the year during the study period. Influenza vaccination was effective in preventing influenza-associated hospitalizations in children of all ages. Influenza VE was higher in younger children than in older children, and higher against hospitalization due to influenza A(H1N1)pdm09 than A(H3N2) and B. CONCLUSIONS: The childhood influenza vaccination program in Hong Kong has prevented influenza-associated hospitalizations particularly in younger children. Our findings support the use of influenza vaccines in children as an effective approach to influenza control and prevention.

Influenza vaccination effectiveness in preventing influenza hospitalization in children, Hong Kong, winter 2019/20.

The winter influenza season 2019/20 in Hong Kong was predominated by influenza A(H1N1)pdm09. We analysed an on-going test-negative design study consisting of 1227 children admitted for febrile acute respiratory illness from 3 November 2019 (week 45) to 21 March 2020 (week 12). We estimated influenza vaccine effectiveness of 65% (95% CI: 46 - 78) against hospitalization due to influenza A and B combined, and 74% (95% CI: 54 - 85) against hospitalization due to influenza A(H1N1)pdm09.