Universal Influenza Vaccines: Progress in Achieving Broad Cross-Protection In Vivo

Abstract

Despite all we have learned since 1918 about influenza virus and immunity, available influenza vaccines remain inadequate to control outbreaks of unexpected strains. Universal vaccines not requiring strain matching would be a major improvement. Their composition would be independent of predicting circulating viruses and thus potentially effective against unexpected drift or pandemic strains. This commentary explores progress with candidate universal vaccines based on various target antigens. Candidates include vaccines based on conserved viral proteins such as nucleoprotein and matrix, on the conserved hemagglutinin (HA) stem, and various combinations. Discussion covers the differing evidence for each candidate vaccine demonstrating protection in animals against influenza viruses of widely divergent HA subtypes and groups; durability of protection; routes of administration, including mucosal, providing local immunity; and reduction of transmission. Human trials of some candidate universal vaccines have been completed or are underway. Interestingly, the HA stem, like nucleoprotein and matrix, induces immunity that permits some virus replication and emergence of escape mutants fit enough to cause disease. Vaccination with multiple target antigens will thus have advantages over use of single antigens. Ultimately, a universal vaccine providing long-term protection against all influenza virus strains might contribute to pandemic control and routine vaccination.

Figure 1.

Diagram of the influenza virus, indicating major protein components. Hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), matrix 1 (M1), and matrix 2 (M2) are the main target antigens proposed for universal vaccines. NEP, nuclear export protein; NS2, nonstructural protein 2; PA, acidic polymerase; RNP, ribonucleoprotein.

Figure 2.

Phylogenetic tree of hemagglutinin sequences, showing different influenza A virus subtypes in groups 1 and 2, and influenza B lineages, based on amino acid sequences. Reproduced from Figure 1 of Jang et al. (156), available by open access and subject to Creative Commons license https://creativecommons.org/licenses/by-nc-sa/3.0/.

Figure 3.

Comparison of sterilizing immunity with infection-permissive immunity. The diagram depicts the differing consequences of types of vaccination. Upper box: Classical vaccine induces antibodies that neutralize virus, preventing infection by a matched virus strain. Lower box: Nucleoprotein plus matrix (NP + M) universal vaccine induces nonneutralizing immune responses that partially control infection and reduce the severity of disease, but allow some degree of viral replication. The consequences can differ in a subsequent year when a new viral strain is encountered.