Influenza Challenge Study Yields Lower Than Expected Results

A new challenge virus for Influenza A (H3N2) failed to meet expectations, but investigators say it will still prove useful in the development of better—and eventually universal—flu vaccines.

Investigators from the National Institutes of Health sought to characterize a wild-type Influenza A/Bethesda/MM1/H3N2 challenge virus by administering it in escalating doses to 37 healthy volunteers and closely monitoring its impact.

Alison Han, MD, MS, the study’s lead author, said influenza challenge studies have a long history and several advantages compared to natural history studies.

“Compared to a natural history study, a challenge study provides the opportunity to know the exact dose and timing of influenza infection so that the timeline of symptoms, shedding, and immune response can be studied in a monitored setting,” Han, a staff clinician in the National Institute of Allergy and Infectious Diseases’ Laboratory of Infectious Diseases, told MD Magazine®.

She noted that natural history studies require a patient to notice symptoms and be diagnosed by a doctor before investigators can include them in a study.

“By then, we have missed the ability to study the beginning part of the illness that may include the initial symptoms, initial shedding, and initial immune response,” she said.

In the new study, patients were given the virus intranasally and then monitored at the NIH’s Clinical Center for no fewer than 9 days. Of the 37 patients, 16 experienced viral shedding, and 27 developed symptoms. A total of 12 patients experienced mild to moderate influenza disease (MMID), the primary endpoint of the study. Only patients who received one of the 2 highest doses experienced MMID. Viral shedding occurred on days 1 and 2 after infection, and symptoms tended to peak at day 3.

Finally, the researchers reported that just 10 patients had at least a fourfold increase of hemagglutinin inhibition (HAI) antibody titer. Han said the results were lower than the MMID rates achieved in previous studies with an H1N1 challenge virus.

“The goal was to reach 60% MMID which we did not achieve, however we were still able to learn much about symptoms, shedding, and immune response after Influenza A H3N2 challenge,” she said.

Though the MMID rate didn’t meet their expectations, Han said researchers can still use the challenge virus in flu vaccine studies if they appropriately adjust their study populations based on the results of this study.

“For example, if we are evaluating a vaccine candidate, having an adequate sample size based on the expectation of how much MMID the virus will likely cause will offer the opportunity to explore the efficacy of the vaccine candidate in a large enough sample size,” she said.

Han said investigators will conduct further research to try to understand why this challenge virus did not work as well. That information could help them better understand influenza more broadly, which could be beneficial in the longer-term question to develop a universal flu vaccine.

“We will also be expanding upon our current repertoire of available influenza challenge viruses by looking at other Influenza A H3N2 strains as well as other subtypes of influenza to help evaluate universal vaccine candidates,” she said.

The study, “A Dose Finding Study of a Wild-Type Influenza A/H3N2 virus in a Healthy Volunteer Human Challenge,” was published in Clinical Infectious Diseases.