Abstract
The 2009 H1N1 influenza (Pdm09) pandemic has been referred to as the first influenza pandemic of the twenty-first century. There is a marked difference in antigenicity between the pandemic H1N1 virus and past seasonal H1N1 viruses, which allowed the pandemic virus to spread rapidly in humans. Antibodies (Abs) against hemagglutinin (HA), especially neutralizing Abs against epitopes in the head of HA, play critical roles in defending the host against the virus. Some preexisting neutralizing Abs that recognize neutralizing epitopes of Pdm09 HA, thereby affording cross-protection, have been reported. To better understand the protective effects of epitopes in Pdm09 HA, we constructed a series of plasmid DNAs (DNA vaccines) by cloning various combinations of Pdm09 neutralizing epitopes into the HA backbone derived from A/PR/8/1934 (H1N1). We subsequently compared the protective immune responses induced by these various forms of HA in a mouse model. We found that the plasmid DNAs with epitope substitutions provided better protection against lethal virus challenge and induced higher strain-specific antibody titers, with epitope Sa being the most effective. Moreover, the combination of epitopes Sa and Sb provided almost complete protection in mice. These findings provide new insights into the protective efficacy of neutralizing epitopes of influenza HA.
Highlights
Influenza presents a significant negative impact on public health
We addressed two questions: could the other four neutralizing epitopes confer protection against the pandemic virus infection? Is there any difference between these epitopes with respect to protective efficacy? To this end, we constructed a series of plasmid DNAs (DNA vaccines) by replacing one or two epitopes of the PR8 HA with epitopes derived from the Pdm09 HA
Amino acid sequence analysis of the Pdm09 HA and the PR8 HA showed some mutations in their neutralizing epitopes (Table 1), crystal structure analysis revealed that the overall structures of the HA proteins were almost identical [26, 27]
Summary
Influenza presents a significant negative impact on public health. Both seasonal influenza epidemics and occasional outbreaks of global pandemics can result in high morbidity and mortality rates [1]. In 2009, a new influenza pandemic emerged and quickly spread to 214 countries [2]. The pathogen of this first influenza pandemic in the twenty-first century was identified as a novel influenza A virus (Pdm09), a triple-reassortant of human, bird, and swine influenza viruses [3]. The entry of the virus to the host cells is mediated by the major envelope glycoprotein hemagglutinin (HA), a surface viral protein and primary target of protective humoral immune responses [6].
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