Considerations on Test-Negative Design for Mpox Risk and Vaccine Efficacy

Overview

The test-negative design (TND) has been proposed to study vaccine effectiveness and risk factors during the 2022 global mpox outbreak. However, challenges such as stigma affecting healthcare-seeking behavior and differences in differential diagnoses limit the validity of TND in this context. The article discusses these caveats and potential strategies to improve TND application for mpox.

Background

The TND is a case-control study design commonly used to estimate vaccine effectiveness by comparing vaccinated proportions among symptomatic individuals who test positive versus negative for a disease. It reduces bias from healthcare-seeking behavior by selecting controls from symptomatic test-negative individuals. Mpox, a viral disease with acute skin lesions, emerged globally in 2022 with transmission primarily via close contact, especially sexual exposure. Diagnosis relies on PCR testing of lesions, and differential diagnoses include other viral infections causing skin lesions. The outbreak context and mpox characteristics pose unique challenges for TND application.

Data Highlights

Mpox test positivity rates among symptomatic individuals meeting case definitions were >60% early in the outbreak and around 20% in later estimates. Testing policies vary by country, influencing selection bias. The TND assumes similar healthcare-seeking behavior among cases and controls, which may be violated due to stigma associated with mpox. Differential diagnoses differ markedly from mpox and may not be fully captured in epidemiologic databases.

Key Findings

• The TND relies on the assumption that cases and controls have similar healthcare-seeking behavior, which is challenged in mpox due to stigma affecting testing and care access.
• Differential diagnoses for mpox involve distinct clinical presentations that may be easily distinguished by clinicians or patients but are underrepresented in databases, complicating control selection.
• Variation in testing policies across countries introduces selection bias, affecting the representativeness of tested populations.
• Mpox’s acute skin lesion presentation and short symptomatic period differ from respiratory illnesses where TND has been traditionally applied, limiting direct extrapolation.
• Despite limitations, TND could be adapted with careful consideration of biases and improved data collection to study mpox vaccine effectiveness and risk factors.

Clinical Implications

Clinicians and researchers should be cautious when interpreting TND-based studies of mpox due to potential biases from differential healthcare-seeking behavior and incomplete capture of alternative diagnoses. Enhanced surveillance and standardized testing criteria may improve the validity of TND analyses. Understanding these limitations is critical for accurate assessment of vaccine effectiveness and risk factors during mpox outbreaks.

Conclusion

While the TND offers advantages for rapid outbreak analysis, its application to mpox is limited by stigma-related healthcare-seeking biases and diagnostic challenges. Addressing these issues is essential to harness the TND effectively for mpox epidemiology and vaccine evaluation.

References

1. Author/Source/2023 -- Considerations on the Use of Test-Negative Design for Analyzing Mpox Risk Factors and Vaccine Efficacy