Influenza A Reinfection in Sequential Human Challenge: Implications for Protective Immunity and "Universal" Vaccine Development

Abstract

Background: Identification of correlates of protection against human influenza A virus infection is important in development of broadly protective ("universal") influenza vaccines. Certain assumptions underlie current vaccine developmental strategies, including that infection with a particular influenza A virus should offer long-term or lifelong protection against that strain, preventing reinfection. In this study we report observations made when 7 volunteers participated in sequential influenza challenge studies where they were challenged intranasally using the identical influenza A(H1N1)pdm09 virus approximately 1 year apart. We evaluate and describe the outcomes of these 7 rechallenge participants and discuss what these results may suggest about correlates of protection and development of more broadly protective influenza vaccines.

Methods: Seven participants were enrolled in 2 viral challenge studies at 7.5- to 18.5-month intervals. Both challenge studies used the identical lot of influenza A (H1N1)pdm09 virus administered intranasally. We evaluated pre- and postchallenge hemagglutination inhibition, neuraminidase inhibition, and stalk antibody titers; peripheral blood leukocyte host gene expression response profiles; daily viral detection via nasal wash; and clinical signs and symptoms.

Results: At least 3 of 7 participants demonstrated confirmed laboratory evidence of sequential infection, with 5 of 7 demonstrating clinical evidence.

Conclusions: The data presented in this report demonstrate that sequential infection with the identical influenza A virus can occur and suggest it may not be rare. These data raise questions about immune memory responses in an acute superficial respiratory mucosal infection and their implications in development of broadly protective influenza vaccines. Further investigation of these observations is warranted.

Clinical trials registration: NCT01646138; NCT01971255.

Keywords: CHIM; challenge; healthy volunteer; influenza A; vaccine.

Figure 1.

Expression of type I interferon (IFN), T-cell, and B-cell signaling genes during A(H1N1)pdm09 influenza challenge 1 and challenge 2. Heatmap diagram showing expression profiles of type I IFN, T-cell, and B-cell signaling immune response pathway genes. For each participant, gene expression analysis was performed by expression microarray, and gene expression on days post–viral challenge was normalized to each participant’s baseline (day 0) expression values. Expression of genes shown in red was increased, and expression of genes shown in green was decreased relative to each participant’s day 0 expression, with black indicating no relative change in expression following A(H1N1)pdm09 virus inoculation. Each participant’s preexisting neuraminidase inhibition (NAI) and hemagglutination inhibition (HAI) titers, daily symptom score, viral shedding status, and clinical outcome (mild to moderate influenza disease [MMID] or no MMID) and challenge 50% tissue culture infectious dose (TCID₅₀) are also shown. Global gene expression analysis was not performed in challenge 1 for participant 7 who received a 10³ TCID₅₀ dose due to the absence of samples.