Next-Generation Influenza Vaccines

Abstract

Most currently used conventional influenza vaccines are based on 1940s technology. Advances in vaccine immunogen design and delivery emerging over the last decade promise new options for improving influenza vaccines. In addition, new technologies for immune profiling provide better-defined immune correlates of protection and precise surrogate biomarkers for vaccine evaluations. Major technological advances include single-cell analysis, high-throughput antibody discovery, next-generation sequencing of antibody gene transcripts, antibody ontogeny, structure-guided immunogen design, nanoparticle display, delivery and formulation options, and better adjuvants. In this review, we provide our prospective outlook for improved influenza vaccines in the foreseeable future.

Figure 1.

Visualized summary of target product profile of current and improved influenza vaccines. Conventional vaccines (current influenza vaccines) confer protection against antigenically matched seasonal influenza viruses. Vaccine efficacy varies year by year. An example of high-performance seasonal vaccines would be one that offers better protective immunity to antigenically matched seasonal influenza viruses, even though they may not provide durable multiyear protection nor protection against mismatched or pandemic viruses. An example of a supraseasonal vaccine would be one that provides consistent protection against antigenically drifted (mismatched) viruses and offers multiyear protection beyond a single influenza season, but may have limited efficacy against pandemic strains. Prepandemic stockpile vaccines (conventional) would work only if the pandemic virus is closely related to the stockpile vaccine strain. An example of a vaccine for pandemic preparedness would be one that provides broad protection against both seasonal and pandemic viruses, although the protective efficacy may not be as high as with strain-matched vaccines. This would allow options for immediate deployment during outbreak with a partially effective intervention. Vaccines for pandemic response would offer potent protection against pandemic viruses as these vaccines would be produced by platform manufacturing technologies using specific sequences from the emerging virus. Universal vaccines are expected to provide robust protection against both seasonal and pandemic viruses over multiple years.

Figure 2.

Expected vaccine efficacy profile of improved seasonal influenza vaccines. Comparison of theoretical vaccine efficacy between the current vaccine and an example of high-performance seasonal vaccine (top). Although average vaccine efficacy over time (${\overline{X}}_{\mathrm{VB}}$) is higher for high-performance seasonal vaccines compared to conventional vaccines, the difference in vaccine efficacy (Δ_VE) between vaccine modalities for each year is consistent and, hence, vaccine efficacy will fluctuate depending on accuracy of antigenic match between vaccine and circulating strains. Theoretical vaccine efficacy of supraseasonal vaccines (bottom). Unlike high-performance seasonal and conventional vaccines, supraseasonal vaccines would provide consistent vaccine efficacy year to year so ${\overline{X}}_{\mathrm{VB}}$ would remain high with no fluctuation. Supraseasonal vaccines would not be significantly affected by antigenic mismatch between vaccine and circulating strains, and, therefore, they may not need annual updates of vaccine components and reformulation.

Figure 3.

Potential scenario of an influenza pandemic with different countermeasure options. In the case of an influenza pandemic caused by a new virus with no antigenically matched stockpile vaccines, vaccines for pandemic preparedness and for pandemic response or a combination of the two vaccines could make a substantial impact on the epidemic curve and reduce the cumulative health burden. Vaccines for pandemic preparedness could be deployed as soon as the outbreak spreads locally and is recognized to be caused by a pandemic strain, so medical providers and at-risk population can be immunized before the pandemic peaks (top). Although vaccine efficacy for this type of vaccine may not be optimal, it will provide time for mass production of strain-matched vaccines (pandemic response). Relying on deployment of strain-matched vaccines alone as a pandemic response may not be sufficient as it may not be feasible to produce enough doses in time to substantially impact the epidemic (middle). This situation will be mitigated as newer technologies for rapid vaccine production such as mRNA-based modalities become available. Sequential deployment of vaccines for pandemic preparedness and pandemic response would be ideal to contain pandemic with minimum burden taking into account the importance of both speed and specificity (bottom).