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NEJM Evid
. 2025 Nov 19:EVIDoa2500087.
doi: 10.1056/EVIDoa2500087. Online ahead of print. Human Challenge Trial of a Nucleoside-Modified Messenger Ribonucleic Acid Influenza Vaccine
Kelly A Lindert 1 , Alex Mann 2 , Anita Geevarughese 3 , Teresa Hauguel 3 , Sarah Mirza 4 , Melissa Bevan 2 , Kevin Yi 5 , Kayleigh Wolfe 6 , Pascale Nantermet 5 , Kingsley Eze 2 , Pratiksha Dokhe 2 , Agnieszka M Zareba 5 , Emily Gomme 3 , Andrew P Catchpole 2 , Annaliesa S Anderson 3 , Alejandra Gurtman 3 , Pirada Suphaphiphat Allen 3
Affiliations
Background: Human challenge trials evaluate protection from influenza exposure following vaccination but have not been reported for nucleoside-modified messenger ribonucleic acid (modRNA) influenza vaccines.
Methods: This phase 2a, double-blind trial randomly assigned healthy adults 18-55 years of age in a 1:1 ratio to receive either a modRNA or quadrivalent influenza vaccine (QIV) 30 days before an influenza A/H1N1 challenge. Control group participants from a separate trial were exposed to the same virus but were not vaccinated. Four primary efficacy end points were used to evaluate events from day 1 to 8 postchallenge. Two end points were the percentage of participants with laboratory-confirmed symptomatic influenza (grade 2 or higher) and the percentage with febrile influenza (with a temperature of at least 37.9°C). Influenza end points were compared between vaccine and control groups to calculate vaccine efficacy (VE [1 minus relative risk]). Two end points were the median differences between the vaccine and control groups for the area under the viral load (VL)-time curve (VL-AUC) and for peak VL. Vaccine safety end points were examined.
Results: The per-protocol cohort included 55, 48, and 52 participants in the modRNA, QIV, and control groups, respectively. Symptomatic influenza occurred in 0%, 4.2%, and 26.9% of participants in the modRNA, QIV, and control groups, respectively, with a VE of 100.0% (95% confidence interval [CI], 75.2% to 100.0%) for the modRNA vaccine and 84.5% (95% CI, 43.4% to 96.0%) for the QIV. Febrile influenza occurred in 0%, 0%, and 17.3% of participants in the modRNA, QIV, and control groups, respectively, with a VE of 100.0% (95% CI, 61.2% to 100.0%) for the modRNA vaccine and 100.0% (95% CI, 55.9% to 100.0%) for the QIV. The median differences in the VL-AUC between the vaccine and control groups were -88.66 for the modRNA (95% CI, -261.95 to -1.35) and -67.01 for the QIV (95% CI, -254.13 to -0.97). The median differences in peak VL between the vaccine and control groups were -4.52 for the modRNA vaccine (95% CI, -5.29 to 0.00) and -1.49 for the QIV (95% CI, -5.25 to 0.00). No serious adverse events were reported.
Conclusions: Following an influenza challenge, the modRNA vaccine was associated with greater VE and reduced VL compared with the control, without any serious adverse events. (Funded by hVIVO and Pfizer; clinical trial registration number, ISRCTN13789612.).
. 2025 Nov 19:EVIDoa2500087.
doi: 10.1056/EVIDoa2500087. Online ahead of print. Human Challenge Trial of a Nucleoside-Modified Messenger Ribonucleic Acid Influenza Vaccine
Kelly A Lindert 1 , Alex Mann 2 , Anita Geevarughese 3 , Teresa Hauguel 3 , Sarah Mirza 4 , Melissa Bevan 2 , Kevin Yi 5 , Kayleigh Wolfe 6 , Pascale Nantermet 5 , Kingsley Eze 2 , Pratiksha Dokhe 2 , Agnieszka M Zareba 5 , Emily Gomme 3 , Andrew P Catchpole 2 , Annaliesa S Anderson 3 , Alejandra Gurtman 3 , Pirada Suphaphiphat Allen 3
Affiliations
- PMID: 41259791
- DOI: 10.1056/EVIDoa2500087
Background: Human challenge trials evaluate protection from influenza exposure following vaccination but have not been reported for nucleoside-modified messenger ribonucleic acid (modRNA) influenza vaccines.
Methods: This phase 2a, double-blind trial randomly assigned healthy adults 18-55 years of age in a 1:1 ratio to receive either a modRNA or quadrivalent influenza vaccine (QIV) 30 days before an influenza A/H1N1 challenge. Control group participants from a separate trial were exposed to the same virus but were not vaccinated. Four primary efficacy end points were used to evaluate events from day 1 to 8 postchallenge. Two end points were the percentage of participants with laboratory-confirmed symptomatic influenza (grade 2 or higher) and the percentage with febrile influenza (with a temperature of at least 37.9°C). Influenza end points were compared between vaccine and control groups to calculate vaccine efficacy (VE [1 minus relative risk]). Two end points were the median differences between the vaccine and control groups for the area under the viral load (VL)-time curve (VL-AUC) and for peak VL. Vaccine safety end points were examined.
Results: The per-protocol cohort included 55, 48, and 52 participants in the modRNA, QIV, and control groups, respectively. Symptomatic influenza occurred in 0%, 4.2%, and 26.9% of participants in the modRNA, QIV, and control groups, respectively, with a VE of 100.0% (95% confidence interval [CI], 75.2% to 100.0%) for the modRNA vaccine and 84.5% (95% CI, 43.4% to 96.0%) for the QIV. Febrile influenza occurred in 0%, 0%, and 17.3% of participants in the modRNA, QIV, and control groups, respectively, with a VE of 100.0% (95% CI, 61.2% to 100.0%) for the modRNA vaccine and 100.0% (95% CI, 55.9% to 100.0%) for the QIV. The median differences in the VL-AUC between the vaccine and control groups were -88.66 for the modRNA (95% CI, -261.95 to -1.35) and -67.01 for the QIV (95% CI, -254.13 to -0.97). The median differences in peak VL between the vaccine and control groups were -4.52 for the modRNA vaccine (95% CI, -5.29 to 0.00) and -1.49 for the QIV (95% CI, -5.25 to 0.00). No serious adverse events were reported.
Conclusions: Following an influenza challenge, the modRNA vaccine was associated with greater VE and reduced VL compared with the control, without any serious adverse events. (Funded by hVIVO and Pfizer; clinical trial registration number, ISRCTN13789612.).