Dengue virus controlled human challenge reveals that preexisting immunity shapes viral replication and broadly protective responses.
Camila D Odio, Rosemary A Aogo, Saba Firdous et al.
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In 30 seconds
This phase 1 controlled human challenge trial enrolled 45 healthy adults to examine how preexisting immunity shapes responses to heterotypic dengue virus challenge. Secondary infection was associated with greater viremia, neutralizing antibody responses, and protective T cell responses than primary or tertiary infection. Baseline immune profiles also distinguished outcomes: antibodies that enhanced viral replication in vitro were associated with delayed immune activation and the highest viremia, whereas antibodies to nonstructural protein 1 across serotypes were associated with earlier interferon responses, viral control, and enduring B and T cell responses. Clinical signs and symptoms associated with viremia were mild.
Key findings
- Secondary infection challenge produced greater viremia, neutralizing antibodies, and protective T cell responses than primary and tertiary infection.
- Baseline antibodies that most efficiently enhanced dengue replication in vitro were associated with delayed immune activation and the highest viremia.
- Higher baseline antibodies to nonstructural protein 1 across multiple serotypes predicted early interferon responses, viremia control, and enduring potent B and T cells.
- Participants with potent neutralizing antibodies and IFN-γ+ T cells at baseline had minimal viral replication.
Why it matters
The findings show that dengue immune history is not captured by antibody levels alone: baseline antibody function and cellular responses were associated with markedly different viral and immune trajectories. Controlled human challenge may help clarify how coordinated or dysregulated responses relate to viral replication and lasting immunity, providing evidence relevant to the design of dengue vaccines and to investigation of immune responses in other viral diseases.
What to keep in mind
The phase 1 trial involved 45 healthy adults and used a controlled challenge with an attenuated virus; findings may not represent naturally acquired dengue infection or clinical disease.