Protection against Divergent Influenza H1N1 Virus by a Centralized Influenza Hemagglutinin

Abstract

Influenza poses a persistent worldwide threat to the human population. As evidenced by the 2009 H1N1 pandemic, current vaccine technologies are unable to respond rapidly to this constantly diverging pathogen. We tested the utility of adenovirus (Ad) vaccines expressing centralized consensus influenza antigens. Ad vaccines were produced within 2 months and protected against influenza in mice within 3 days of vaccination. Ad vaccines were able to protect at doses as low as 107 virus particles/kg indicating that approximately 1,000 human doses could be rapidly generated from standard Ad preparations. To generate broadly cross-reactive immune responses, centralized consensus antigens were constructed against H1 influenza and against H1 through H5 influenza. Twenty full-length H1 HA sequences representing the main branches of the H1 HA phylogenetic tree were used to create a synthetic centralized gene, HA1-con. HA1-con minimizes the degree of sequence dissimilarity between the vaccine and existing circulating viruses. The centralized H1 gene, HA1-con, induced stronger immune responses and better protection against mismatched virus challenges as compared to two wildtype H1 genes. HA1-con protected against three genetically diverse lethal influenza challenges. When mice were challenged with 1934 influenza A/PR/8/34, HA1-con protected 100% of mice while vaccine generated from 2009 A/TX/05/09 only protected 40%. Vaccination with 1934 A/PR/8/34 and 2009 A/TX/05/09 protected 60% and 20% against 1947 influenza A/FM/1/47, respectively, whereas 80% of mice vaccinated with HA1-con were protected. Notably, 80% of mice challenged with 2009 swine flu isolate A/California/4/09 were protected by HA1-con vaccination. These data show that HA1-con in Ad has potential as a rapid and universal vaccine for H1N1 influenza viruses.

Intranasal immunization with influenza antigens conjugated with cholera toxin subunit B stimulates broad spectrum immunity against influenza viruses

“…It is also known that conserved or centralized HA2 induces cross protection. 3,6,29,30 Thus, incorporation of a highly conserved HA2 sequence could only strengthen a vaccine strategy to stimulate broad-based immunity and protection. Previous studies also show that CTB can be used in the design of influenza vaccines to enhance immune responses and that CTB alone does not elicit significant protection against lethal influenza viral challenge.…”

“…It is alarming that vaccine mismatches occurred at around 50% in United States from 1997 to 2005. 3 Clearly, a universal influenza vaccine that would protect against a majority of circulating or potential epidemic influenza virus strains is pressingly needed. This universal vaccine would obviate the annual reformulation and repeated annual immunization.…”

Replicating Single-Cycle Adenovirus Vectors Generate Amplified Influenza Vaccine Responses

“…While Ad vectors have shown promise as gene-based influenza vaccines, the vast majority of these studies have used replication-defective Ad (RD-Ad) vectors (28–34). When one RD-Ad vector infects a cell, it carries only one copy of an influenza virus antigen and expresses only “1×” protein.…”

CD46-Mediated Transduction of a Species D Adenovirus Vaccine Improves Mucosal Vaccine Efficacy

“…While these modified viruses show lower levels of transduction by the i.n. route, they induced equivalent T cell immunity (Weaver et al, 2012). The primary receptor for species D Ads is CD46, which is expressed on all human nucleated cells, including dendritic cells, and therefore more readily transduced (Ni et al, 2005).…”