Advancing influenza vaccines: A review of next-generation candidates and their potential for global health impact

Abstract

Background: Influenza vaccines are an essential tool for influenza prevention, control and preparedness. However, demand for them and their programmatic suitability globally is significantly influenced by their variable effectiveness against influenza illness annually, limited duration of protection and need for yearly updating and vaccination. As such, the World Health Organization and major funders, such as the United States National Institute of Allergy and Infectious Diseases and Bill and Melinda Gates Foundation, have strongly encouraged developing influenza vaccines with increased efficacy, breadth and duration of protection. Here, we review the next-generation influenza vaccine pipeline, focusing on products in clinical development, and compare their characteristics to currently approved seasonal influenza vaccines.

Methods: To identify and characterize next-generation influenza vaccine candidates, we conducted a comprehensive literature review, using the CIDRAP Universal Influenza Vaccine Technology Landscape as a primary reference source and extracting additional information from peer-reviewed manuscripts, clinical trial records and other media in the public domain.

Results: Our analysis reveals a robust clinical development pipeline for next-generation influenza vaccines, featuring a diversity of approaches to address existing vaccine challenges and several candidates in advanced stages of development. mRNA vaccines emerged as a predominant platform, as evidenced by the number of candidates focused on improved seasonal protection as well as combination vaccine candidates targeting additional respiratory viruses.

Conclusion: While still early in development, results from universal or broadly protective products are promising and warrant continued investment from funders. As most Phase 3 candidates are mRNA-based and include combination vaccines, it is critical to begin considering how these new products may become integrated into the current global influenza vaccine strain selection and manufacturing ecosystems, and existing immunization programmes.

Trial registration: ClinicalTrials.gov NCT04960397 NCT03553940.

Keywords: Broadly protective influenza vaccines; Improved influenza vaccines; Influenza vaccines; Next-generation influenza vaccines; Universal influenza vaccines.

Fig. 1

Framework of improving influenza vaccines. Traditional seasonal influenza vaccines serve as a baseline for improvement and include standard dose, egg- and cell-based inactivated and live-attenuated influenza virus vaccines that are designed for seasonal and strain-specific protection. Improvements in vaccine design or manufacturing are expected to lead or have led to improvements in vaccine performance. Both design or manufacturing and performance improvements in enhanced seasonal influenza vaccines* are moderate (vaccines still target HA but use more antigen, recombinant technology or an adjuvant). Improvements from next-generation influenza vaccines are expected to be greater, using novel vaccine targets and design approaches, including platforms, to result in better efficacy/effectiveness, breadth or duration of protection than currently available influenza vaccines, which includes both traditional and enhanced seasonal vaccines. *Listed order of types of enhanced seasonal vaccines is alphabetical and does not suggest differences in performance)

Fig. 2

The landscape of next-generation influenza vaccines in clinical development, as of April 2024. Each box represents a unique vaccine candidate or group of candidates, associated with their respective developer(s), and includes key characteristics about the candidate, such as indication, route of delivery, high-risk populations tested and antigens included/targeted. Abbreviations: bIRV = bivalent influenza modRNA vaccine; BPL = beta-propriolactone; CIVICs = Collaborative Influenza Vaccine Innovation Centers; HA = haemagglutinin; IIV = inactivated influenza virus vaccine; LAIV = live-attenuated influenza virus vaccine; LNP = lipid nanoparticle; mIRV = monovalent influenza modRNA vaccine; NA = neuraminidase; NIAID = National Institute for Allergy and Infectious Diseases; qIRV = quadrivalent influenza modRNA vaccine; RSV = respiratory syncytial virus; UFV = universal influenza vaccine; VRC = Vaccine Research Center.

Fig. 3

Next-generation influenza vaccines in clinical development tallied by vaccine platform, indication and clinical development phase. (A) The share of each vaccine platform among all next-generation influenza vaccine candidates in clinical development. (B) The number of candidates among universal or broadly protective, next-generation seasonal and combination influenza vaccines, as characterized by vaccine platform. (C) The number of vaccine candidates in or having completed Phase 1, Phase 1/2, Phase 2 or Phase 3 clinical trials, as characterized by vaccine indication.