Background The development of vaccines and therapeutics has relied on healthy volunteer influenza challenge studies. A validated human infection model with wild-type A(H1N1)pdm09 was reported previously. Our objective was to characterize a wild-type influenza A/Bethesda/MM1/H3N2 challenge virus in healthy volunteers. Methods Participants received a single dose of a cell-based, reverse-genetics, Good Manufacturing Practices–produced wild-type influenza A(H3N2)2011 virus intranasally and were isolated at the National Institutes of Health Clinical Center for ≥9 days. Dose escalation was performed from 104 to 107 TCID50 (50% tissue culture infectious dose). Viral shedding and clinical disease were evaluated daily. Results Of 37 participants challenged, 16 (43%) had viral shedding and 27 (73%) developed symptoms, with 12 (32%) participants experiencing mild to moderate influenza disease (MMID), defined as shedding and symptoms. Only participants receiving 106 and 107 TCID50 experienced MMID at 44% and 40%, respectively. Symptom severity peaked on day 3, whereas most viral shedding occurred 1–2 days after challenge. Only 10 (29%) participants had a ≥4-fold rise in hemagglutination inhibition antibody titer after challenge. Conclusions The A/Bethesda/MM1/H3N2 challenge virus safely induced MMID in healthy volunteers, but caused less MMID than the A(H1N1)pdm09 challenge virus even at the highest dose. There was less detection of shedding though the incidence of symptoms was similar to A(H1N1)pdm09. Fewer serum anti-hemagglutinin (HA) antibody responses with less MMID indicate that preexisting immunity factors other than anti-HA antibody may limit shedding in healthy volunteers. This A/Bethesda/MM1/H3N2 challenge virus can be utilized in future studies to further explore pathogenesis and immunity and to evaluate vaccine candidates. Clinical Trials Registration NCT02594189
BackgroundHealthy volunteer challenge studies provide an opportunity to better understand influenza pathogenesis and correlates of protection. The development of vaccines and therapeutics has relied on these studies as will future universal vaccine candidates. The first fully validated wild-type human infection model with A(H1N1)pdm09 was developed at the NIH Clinical Center (CC) in 2012 and this study represents the first validation of a wild-type seasonal H3N2 human infection model. The objective of this study was to characterize a wild-type Influenza A/Texas-like H3N2 challenge virus in healthy volunteers.MethodsHealthy volunteers were isolated at the NIH CC for a minimum of 9 days. Subjects received a single dose of a reverse genetics, cell-based, GMP, wild-type A H3N2 virus intranasally. Dose escalation was performed from 104 to 107 TCID50. Viral shedding and clinical disease were evaluated daily, including clinician assessments and a validated patient-reported outcome tool, FLU-PRO©.ResultsA total of 37 subjects were challenged. Sixteen (43%) subjects had viral shedding and 27 (73%) developed influenza symptoms, with 12 subjects (32%) experiencing mild-to-moderate influenza disease (MMID) defined as symptoms and shedding. Only subjects receiving the 106 and 107 TCID50 doses experienced MMID at 44% and 40%, respectively. Nose and throat symptoms were most common and peaked by Days 2–3 post-challenge. Although serum antibody responses were observed, many of these responses were limited in a significant number of subjects.ConclusionThe A/Texas-like H3N2 Influenza challenge virus safely induced MMID in healthy volunteers, but was less effective than the A(H1N1)pdm09 challenge virus. This lower MMID rate of 40% was observed at the 107 TCID50 dose and was driven by less detection of shedding as the incidence of symptoms was similar to A(H1N1)pdm09. The limited serum antibody responses observed demonstrate that preexisting immunity in healthy volunteers against the seasonal H3N2 lineage may limit shedding compared with the more recently emerged seasonal A(H1N1)pdm09 lineage. The successful characterization of this H3N2 model makes future studies using this model to explore viral pathogenesis or evaluate vaccines possible.This research was supported by the Intramural Research Program of the NIH, NIAID.Disclosures All authors: No reported disclosures.
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