Simultaneous Targeting of Multiple Hemagglutinins to APCs for Induction of Broad Immunity against Influenza

Abstract

There is a need for vaccines that can confer broad immunity against highly diverse pathogens, such as influenza. The efficacy of conventional influenza vaccines is dependent on accurate matching of vaccines to circulating strains, but slow and limited production capacities increase the probability of vaccine mismatches. In contrast, DNA vaccination allows for rapid production of vaccines encoding novel influenza Ags. The efficacy of DNA vaccination is greatly improved if the DNA-encoded vaccine proteins target APCs. In this study, we have used hemagglutinin (HA) genes from each of six group 1 influenza viruses (H5, H6, H8, H9, H11, and H13), and inserted these into a DNA vaccine format that induces delivery of the HA protein Ags to MHC class II molecules on APCs. Each of the targeted DNA vaccines induced high titers of strain-specific anti-HA Abs. Importantly, when the six HA vaccines were mixed and injected simultaneously, the strain-specific Ab titers were maintained. In addition, the vaccine mixture induced Abs that cross-reacted with strains not included in the vaccine mixture (H1) and could protect mice against a heterosubtypic challenge with the H1 viruses A/Puerto Rico/8/1934 (H1N1) and A/California/07/2009 (H1N1). The data suggest that vaccination with a mixture of HAs could be useful for induction of strain-specific immunity against strains represented in the mixture and, in addition, confer some degree of cross-protection against unrelated influenza strains.

A DNA Vaccine That Encodes an Antigen-Presenting Cell-Specific Heterodimeric Protein Protects against Cancer and Influenza

“…Supporting this possibility, introducing a mixture of six different group 1 HAs (H5, H6, H8, H9, H11, H13) into the C H 3-based homodimeric format resulted in protection of immunized mice against a heterosubtypic H1N1 challenge, suggesting that dilution of strain-specific epitopes can result in preferential stimulation of B cells specific for conserved, immunosubdominant epitopes. 34 A recent publication of Kanekiyo et al 40 using nanoparticles that express eight different H1 HAs support such a dilutional strategy for induction of antibodies against subdominant epitopes. Finally, utilization of different dimerization motifs should offer the possibility of delivering two distinct APC-targeting DNA vaccines simultaneously.…”

“…Theoretically, C H 3-based homodimerization in the endoplasmic reticulum (ER) of transfected cells should give three types of molecules that express HA PR8 /HA PR8 , HA PR8 /HA Cal07 , and HA Cal07 /HA Cal07 in a 1:2:1 ratio. 34 The immunized mice were boosted after 5 weeks and PR8and Cal07-specific IgGs were measured 2 weeks after the boost. The (A-D) Targeting units, dimerization units, and antigenic units are indicated by symbols (given in boxes).…”

Recombinant Influenza Vaccines: Saviors to Overcome Immunodominance

“…One of the antibodies generated after immunization, 441D6, binds to a conserved epitope, which lies opposite to RBS and protects against H1N1 strains spanning from 1977 to 2009 (113,114). Anderson et al generated cross-reactive antibody responses by injecting a mix of DNA vaccines containing HA genes from six members of group 1 IAV, which was further enhanced by inclusion of an antigen presenting cell targeting unit specific for MHCII, thus favoring BCR cross-linking (115). Another strategy to elicit broadly reactive antibodies within IAV subtypes is to use computationally optimized broadly reactive antigens (COBRA), which are displayed on virus like particles or expressed in live attenuated influenza vaccine.…”

Influenza Virus-like Particle (VLP) Vaccines Expressing the SARS-CoV-2 S Glycoprotein, S1, or S2 Domains

“…As such, unraveling the function of these non-neutralizing antibodies and their involvement in protection against SARS-CoV-2 could be beneficial. Additionally, since multi-antigenic vaccines have been reported to confer broader and enhanced protection compared to single antigen vaccines against various diseases [ 49 , 50 , 51 ], combining S1 and S2 epitopes may also be a potential vaccination strategy. Further studies assessing the VLP vaccine efficacy using animal models such as ferrets and Syrian golden hamsters would be ideal for in vivo studies since these animals are susceptible to SARS-CoV-2 with clinical symptoms and pathogenicity being not too dissimilar to those found in humans [ 52 , 53 ].…”