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A Dose-finding Study of a Wild-type Influenza A(H3N2) Virus in a Healthy Volunteer Human Challenge Model.

ABSTRACT: 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.

SUBMITTER: Han A

PROVIDER: S-EPMC6880340 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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A Dose-finding Study of a Wild-type Influenza A(H3N2) Virus in a Healthy Volunteer Human Challenge Model.

Han Alison A Czajkowski Lindsay M LM Donaldson Amanda A Baus Holly Ann HA Reed Susan M SM Athota Rani S RS Bristol Tyler T Rosas Luz Angela LA Cervantes-Medina Adriana A Taubenberger Jeffery K JK Memoli Matthew J MJ

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20191101 12

<h4>Background</h4>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.<h4>Methods</h4>Participants received a single dose of a cell-based, reverse-genetics, Good Manufacturing Practices-produced wild-type influenza A(H3N2)2011 virus intranasall ...[more]

PMID: 30770534

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Project description:Influenza virus hemagglutinin (HA) surface glycoprotein is currently the primary target of licensed influenza vaccines. Recently, broadly reactive antibodies that target the stalk region of the HA have become a major focus of current novel vaccine development. These antibodies have been observed in humans after natural infection with influenza A virus, but the data are limited. Using samples and data from the uniquely controlled setting of an influenza A/H1N1 virus human challenge study of healthy volunteers, we performed a secondary analysis that for the first time explores the role of anti-HA stalk antibody as a human correlate of protection. An anti-HA stalk antibody enzyme-linked immunosorbent assay (ELISA) was performed on samples from 65 participants challenged with a 2009 H1N1pdm virus. Pre- and postchallenge anti-HA stalk titers were then correlated with multiple outcome measures to evaluate anti-HA stalk antibody titer as a correlate of protection. Anti-HA stalk antibody titers were present before challenge and rose in response to challenge in 64% of individuals. Those individuals with higher titers at baseline were less likely to develop shedding, but not less likely to develop symptoms. Similar to the hemagglutination inhibition (HAI) titer, the baseline anti-HA stalk antibody titer did not independently predict a decrease in the severity of influenza disease, while the antineuraminidase (neuraminidase inhibition [NAI]) titer did. As a correlate of protection, the naturally occurring anti-HA stalk antibody titer is predictive of a reduction of certain aspects of disease similar to HAI titer, but the NAI titer is the only identified correlate that is an independent predictor of a reduction of all assessed influenza clinical outcome measures.IMPORTANCE This is the first study to evaluate preexisting anti-HA stalk antibodies as a predictor of protection. We use a healthy volunteer influenza challenge trial for an examination of the role such antibodies play in protection. This study demonstrates that anti-HA stalk antibodies are naturally generated in response to an infection, but there is significant variability in response. Similar to antibodies that target the HA head, baseline anti-HA stalk antibody titer is a correlate of protection in terms of reduced shedding, but it is not a predictor of reduced clinical disease or an independent predictor of disease severity. These results, in the context of the limited data available in humans, suggest that vaccines that induce anti-HA stalk antibodies could play a role in future vaccine strategies, but alone, this target may be insufficient to induce a fully protective vaccine and overcome some of the issues identified with current vaccines.

Dataset Information

A Dose-finding Study of a Wild-type Influenza A(H3N2) Virus in a Healthy Volunteer Human Challenge Model.

Publications

A Dose-finding Study of a Wild-type Influenza A(H3N2) Virus in a Healthy Volunteer Human Challenge Model.

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