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Clin Infect Dis. 2019 Feb 16. pii: ciz141. doi: 10.1093/cid/ciz141. [Epub ahead of print]

A Dose Finding Study of a Wild-Type Influenza A/H3N2 virus in a Healthy Volunteer Human Challenge Model.

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LID Clinical Studies Unit, Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.



The development of vaccines and therapeutics have relied on healthy volunteer influenza challenge studies. A validated human infection model with wild-type A(H1N1)pdm09 was reported previously.


To characterize a wild-type Influenza A/Bethesda/MM1/H3N2 challenge virus in healthy volunteers.


Participants received a single dose of a cell-based, reverse-genetics, GMP-produced wild-type influenza A/H3N2/2011 virus intranasally and were isolated at the NIH Clinical Center for > 9 days. Dose escalation was performed from 104 to 107 TCID50. Viral shedding and clinical disease were evaluated daily.


Of 37 participants challenged, 16 (43%) had viral shedding and 27 (73%) developed symptoms with 12 participants (32%) experiencing mild to moderate influenza disease (MMID) defined as shedding and symptoms. Only participants receiving the 106 and 107 TCID50 doses experienced MMID at 44% and 40%, respectively. Symptom severity peaked on day 3 while most viral shedding occurred 1-2 days after challenge. Only 10 (29%) participants had > fourfold rise in hemagglutinin inhibition (HAI) antibody titer after challenge.


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-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.


Challenge; H3N2; Healthy Volunteer; Influenza A


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