Enhanced durability of a Zika virus self-amplifying RNA vaccine through combinatorial OX40 and 4-1BB agonism

Hsueh-Han Lu; Rúbens Prince dos Santos Alves; Qin Hui Li; Luke Eder; Julia Timis; Henry Madany; Kantinan Chuensirikulchai; Krithik V. Varghese; Aditi Singh; Linda Le Tran; Audrey Street; Annie Elong Ngono; Michael Croft; Sujan Shresta

doi:10.1172/jci.insight.187405

Published April 3, 2025 - More info

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Abstract

The SARS-CoV-2 pandemic highlighted the potential of mRNA vaccines in rapidly responding to emerging pathogens. However, immunity induced by conventional mRNA vaccines wanes quickly, requiring frequent boosters. Self-amplifying RNA (saRNA) vaccines, which extend antigen expression via self-replication, offer a promising strategy to induce more durable immune responses. In this study, we developed an saRNA vaccine encoding Zika virus (ZIKV) membrane and envelope (M/E) proteins and evaluated its efficacy in mice. A single vaccination elicited strong humoral and cellular immune responses and reduced viral loads, but only for 28 days. By day 84, antibody titers and T cell responses had significantly declined, resulting in reduced efficacy. To address this, we evaluated agonist antibodies targeting the T cell costimulatory molecules OX40 and 4-1BB. Co-administration of agonist antibodies enhanced CD8⁺ T cell responses to vaccination, resulting in sustained protection and reduced viral loads at day 84. Depletion and passive transfer studies confirmed that long-term protection was primarily CD8⁺ T cell-dependent, with minimal contributions from antibody responses. These findings suggest that agonists targeting members of the tumor necrosis receptor superfamily, such as OX40 and 4-1BB, might enhance the durability of saRNA vaccine-induced protection, addressing a key limitation of current mRNA vaccine platforms.

Enhanced durability of a Zika virus self-amplifying RNA vaccine through combinatorial OX40 and 4-1BB agonism

Hsueh-Han Lu,¹ Rúbens Prince dos Santos Alves,¹ Qin Hui Li,¹ Luke Eder,¹ Julia Timis,¹ Henry Madany,¹ Kantinan Chuensirikulchai,¹ Krithik V. Varghese,¹ Aditi Singh,¹ Linda Le Tran,¹ Audrey Street,¹ Annie Elong Ngono,¹ Michael Croft,² and Sujan Shresta¹

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Enhanced durability of a Zika virus self-amplifying RNA vaccine through combinatorial OX40 and 4-1BB agonism

Hsueh-Han Lu,1 Rúbens Prince dos Santos Alves,1 Qin Hui Li,1 Luke Eder,1 Julia Timis,1 Henry Madany,1 Kantinan Chuensirikulchai,1 Krithik V. Varghese,1 Aditi Singh,1 Linda Le Tran,1 Audrey Street,1 Annie Elong Ngono,1 Michael Croft,2 and Sujan Shresta1

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Hsueh-Han Lu,¹ Rúbens Prince dos Santos Alves,¹ Qin Hui Li,¹ Luke Eder,¹ Julia Timis,¹ Henry Madany,¹ Kantinan Chuensirikulchai,¹ Krithik V. Varghese,¹ Aditi Singh,¹ Linda Le Tran,¹ Audrey Street,¹ Annie Elong Ngono,¹ Michael Croft,² and Sujan Shresta¹