Vaccination with Vesicular Stomatitis Virus-Vectored Chimeric Hemagglutinins Protects Mice against Divergent Influenza Virus Challenge Strains

Abstract

Seasonal influenza virus infections continue to cause significant disease each year, and there is a constant threat of the emergence of reassortant influenza strains causing a new pandemic. Available influenza vaccines are variably effective each season, are of limited scope at protecting against viruses that have undergone significant antigenic drift, and offer low protection against newly emergent pandemic strains. "Universal" influenza vaccine strategies that focus on the development of humoral immunity directed against the stalk domains of the viral hemagglutinin (HA) show promise for protecting against diverse influenza viruses. Here, we describe such a strategy that utilizes vesicular stomatitis virus (VSV) as a vector for chimeric hemagglutinin (cHA) antigens. This vaccination strategy is effective at generating HA stalk-specific, broadly cross-reactive serum antibodies by both intramuscular and intranasal routes of vaccination. We show that prime-boost vaccination strategies provide protection against both lethal homologous and heterosubtypic influenza challenge and that protection is significantly improved with intranasal vaccine administration. Additionally, we show that vaccination with VSV-cHAs generates greater stalk-specific and cross-reactive serum antibodies than does vaccination with VSV-vectored full-length HAs, confirming that cHA-based vaccination strategies are superior at generating stalk-specific humoral immunity. VSV-vectored influenza vaccines that express chimeric hemagglutinin antigens offer a novel means for protecting against widely diverging influenza viruses. IMPORTANCEUniversal influenza vaccination strategies should be capable of protecting against a wide array of influenza viruses, and we have developed such an approach utilizing a single viral vector system. The potent antibody responses that these vaccines generate are shown to protect mice against lethal influenza challenges with highly divergent viruses. Notably, intranasal vaccination offers significantly better protection than intramuscular vaccination in a lethal virus challenge model. The results described in this study offer insights into the mechanisms by which chimeric hemagglutinin (HA)-based vaccines confer immunity, namely, that the invariant stalk of cHA antigens is superior to full-length HA antigens at inducing cross-reactive humoral immune responses and that VSV-cHA vaccine-induced protection varies by site of inoculation, and contribute to the further development of universal influenza virus vaccines. O n average, there are more than 200,000 hospitalizations due to influenza-associated complications each year in the United States (1), despite the widespread use of seasonal influenza vaccines. Many of these hospitalized patients had received the seasonal vaccine and yet developed disease (2). Recent meta-analysis suggests that the effectiveness of seasonal influenza vaccines is ca. 69% (3), although individual studies report much lower effectiveness for a given influenza season (3). This is in contrast ...

Chikungunya, Influenza, Nipah, and Semliki Forest Chimeric Viruses with Vesicular Stomatitis Virus: Actions in the Brain

“…In contrast, the same intranasal inoculation with VSVΔG-CHIKV (n ϭ 8) and VLV (n ϭ 6) showed complete safety, with all mice surviving to the end of the experiment 42 days postinoculation. Although VSVΔG-H5N1 is nonpathogenic in adult mice outside the brain (45,46), here, we found it to be lethal after intranasal inoculation of P14 mice, with only a single survivor out of a large cohort (n ϭ 23) and almost all the mice succumbing to the virus within 4 to 10 days of inoculation (Fig. 4).…”

“…The VSV glycoprotein gene was deleted (VSVΔG) in four of the viruses, VSVΔG-CHIKV, VSVΔG-H5N1, VSVΔG-Nipah F, and VSVΔG-Nipah G. VLV was generated from the Semliki Forest virus RNA replicon encoding VSV G and the four nonstructural proteins of SFV but none of the SFV structural proteins (37,39). All four recombinants have been tested as possible vaccine vectors (38,(44)(45)(46)(47)(48)(49). Three additional recombinant VSVs were used for control purposes; all three have been previously used to test intracranial safety (18,41,50).…”

“…The chimera incorporated functional CHIKV glycoproteins into the viral envelope in place of VSV G (44). VSVΔG-H5N1 has the VSV G gene deleted, and in its place were substituted the two influenza virus genes, H5 and N1, as described in detail previously (45,46). Genomic diagrams of the recombinant chimeric viruses are shown in Fig.…”

Reassortment of high-yield influenza viruses in vero cells and safety assessment as candidate vaccine strains

“…1,9 In several recent publications, we and other researcher have described screening methods of highly productive vaccine strains in Vero cell. 2,10,11 In this study, we used 2 donors of high-yield influenza viruses in …”

Replicon RNA Viral Vectors as Vaccines

“…Recombinant MV vectors carrying the HA gene have also been applied for vaccination studies [39]. Also VSV vectors have been utilized for vaccine development against influenza virus [40]. Instead of using full-length HA, expression of the stalk domain of HA generated chimeric HA (cHA) antigens.…”