Disease Analysis: Seasonal Influenza Vaccines

Disease Overview

Influenza is an acute respiratory illness caused by influenza viruses belonging to the Orthomyxoviridae family, a group of enveloped viruses with segmented, negative-sense, single-stranded RNA genomes. Two types of influenza virus are predominant in humans, types A and B, which circulate annually between late fall and early spring, causing seasonal epidemics. The virus is transmitted from person to person through the uptake of tiny droplets of aerosolized virus secreted via coughing, sneezing, or talking with an infected person. The virus can also survive on hard surfaces for approximately 24–48 hours and can be acquired by touching contaminated surfaces and subsequently touching the nose or mouth. In the US, the Centers for Disease Control and Prevention (CDC) estimates that influenza causes 9–45 million illnesses annually and is the cause of 12,000 to 61,000 deaths per year.

Latest key takeaways

• The seasonal influenza vaccines market in the US, Japan, and five major European markets (France, Germany, Italy, Spain, and the UK) is expected to continue to expand over the next 10 years, largely due to the continued uptake of premium-priced vaccines in the elderly subgroup, including quadrivalent forms of Fluzone High-Dose (HD) and Fluad, as well as the launch of the first-in-class adjuvanted nanoparticle vaccine, NanoFlu. Further to this, an aging population in the US, Japan, five major European markets, and other developed countries will increase the number of patients in the ≥65 years age group, where coverage rates are higher. Additionally, the COVID-19 pandemic has prompted an unexpected surge in demand for influenza vaccines due to heightened public awareness of the threat posed by respiratory viruses to the elderly and those with co-morbidities, as well as the potential burden on healthcare services of coinciding COVID and influenza waves.
• Three major manufacturers dominate the seasonal influenza vaccines market, namely GlaxoSmithKline, Seqirus, and Sanofi, with 2020 vaccines sales of $1,023m, $952m (June 2019 to June 2020), and $2,953m, respectively. Each company saw increased sales of its portfolio between 2019 and 2020, with GlaxoSmithKline (Fluarix and Flulaval), Seqirus (Afluria, Agrippal, Fluad, and Flucelvax), and Sanofi (Fluzone, Fluzone HD, Vaxigrip, and Flublok) sales growing by 35%, 21%, and 38%, respectively. Additionally, AstraZeneca’s FluMist QIV has recovered its footing in the influenza market, matching its previous peak sales of $295m.
• Vaccines produced by the traditional egg-based method, including Afluria/Agrippal (CSL), Fluarix/Flulaval (GlaxoSmithKline), and Fluzone/Vaxigrip (Sanofi), collectively hold the greatest share of the seasonal influenza market and are primarily used outside of the lucrative elderly subgroup, where other vaccines that have demonstrated superior effectiveness to standard dose inactivated vaccines (Fluzone HD, Fluad, Flucelvax, and Flublok) have been gaining increasing uptake in recent years. As there is no differentiation between the standard dose inactivated vaccines with regard to effectiveness or safety, uptake is primarily based on marketing and manufacturing capabilities, as well as competitive tendering processes. Egg-based vaccines have the disadvantage of long production timelines, and the viral HA antigens are prone to mutations during the egg-based replication process. On the other hand, recombinant or cell-based vaccines have faster production timelines and a reduced risk of HA mutations, leading to potentially superior protection.
• There are two non-egg-based vaccines on the market, Sanofi’s recombinant HA protein vaccine Flublok QIV, and Seqirus’s cell-based vaccine Flucelvax QIV, with the latter having the benefit of a broader label in the US (individuals aged ≥4 years versus aged ≥18 years for Flublok). There is growing evidence that Flublok’s and Flucelvax’s egg-free production process (and subsequent lack of egg-based mutations that can lead to the produced HA antigens differing from those of circulating strains) results in superior real-world effectiveness compared to inactivated egg-based vaccines, particularly in the elderly where vaccine effectiveness is suboptimal. Having gained regulatory approvals in the EU in Q4 2020, both Flucelvax QIV and Flublok QIV are expected to see sales growth. Approval of Flublok QIV in the EU should allow the vaccine to compete against Flucelvax QIV, Fluad QIV, and Sanofi’s own Efluelda QIV from the 2021/22 season in the elderly segment, where all vaccines have shown evidence of increased effectiveness compared to standard dose inactivated vaccines.
• The 2020 EU approvals of CSL’s Fluad QIV and Sanofi’s Fluzone HD QIV mark significant opportunities for both manufacturers. Within Europe, Fluad possesses the first-to-market advantage and benefits from a preferential recommendation for use in the elderly in the UK. Historical manufacturing capacity issues prevented Sanofi from marketing Fluzone HD outside of the US, but after investing in increasing its manufacturing capacity, Sanofi has now decided to market the vaccine in additional regions including Europe, posing a significant threat to Fluad’s European dominance of the elderly segment. Given the lack of head-to-head trials comparing Fluad and Fluzone HD, competitive pricing will be paramount for Fluad to maintain its market share.
• NanoFlu, a first-in-class nanoparticle vaccine, is the most advanced asset in the influenza pipeline. Despite having achieved positive Phase III results, Novavax has not detailed a timeline for the submission of a BLA filing for NanoFlu, with the company’s near-term focus turning to its COVID vaccine, NVX-CoV2373. However, Novavax has previously stated its ongoing commitment to gaining approval for its influenza vaccine, and therefore Datamonitor Healthcare’s base case scenario is that the company will submit a regulatory filing in 2021/22. Assuming a positive response from the FDA, NanoFlu should launch in time for the 2022/23 influenza season. Approval is expected based on a Phase III trial showing superior immunogenicity in the elderly compared to standard dose Fluzone; however, a confirmatory efficacy study post-approval will be required, most probably against Fluzone HD. Based on promising immunogenicity against both vaccine homologous and historically drifted strains, we expect NanoFlu will be a strong competitor for Fluzone HD, Flublok, and Fluad in the elderly segment, but much will depend on the outcome of the confirmatory efficacy study as some physicians/payers will not be willing to infer that improved immunogenicity necessarily results in improved real-world protection.
• There is a high unmet need in the influenza space for a universal influenza vaccine which offers protection against a broader variety of strains, ideally over several seasons, though at this stage it is unclear how long any protective effect would last. Additionally, universal vaccines should be able to provide protection against new pandemic strains that may arise, which the seasonal influenza vaccine is unable to do. Despite positive immunogenicity data from Phase I and Phase II clinical trials, in October 2020 BiondVax reported that its universal vaccine candidate M-001 had failed to demonstrate efficacy in its pivotal Phase III trial. With very limited funding available, BiondVax has decided to shelve M-001 while it tries to identify new pipeline assets in the broader infectious disease space, and we therefore believe continued development of M-001 is very unlikely. Although Imutex’s FLU-v is now the most advanced universal vaccine in development, progress is currently stalled while the company seeks a partner to fund a pivotal trial, and therefore it seems that the earliest a universal vaccine will reach the market is 2024.