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 9–41 million illnesses annually and is the cause of 12,000 to 52,000 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 a 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 GSK, CSL Seqirus, and Sanofi, with Sanofi being the clear market leader, and CSL Seqirus and GSK jostling for second place. Each company saw increased sales of its portfolio between 2019 and 2021, with GSK (Fluarix and Flulaval), CSL Seqirus (Afluria, Agrippal, Fluad, and Flucelvax), and Sanofi (Fluzone, Fluzone HD, Vaxigrip, and Flublok) sales showing unexpected growth in the face of the COVID-19 pandemic. Additionally, AstraZeneca’s FluMist has recovered its footing in the influenza market, matching its previous peak sales of $295m in 2020, though sales dipped to $253m in 2021.
• Vaccines produced by the traditional egg-based method, including Afluria/Agrippal (CSL Seqirus), Fluarix/Flulaval (GSK), and Fluzone/Vaxigrip (Sanofi), collectively hold the greatest share of the seasonal influenza market and are primarily used outside of the lucrative elderly subgroup. Differentiated vaccines, which 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 CSL 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.
• Historical manufacturing capacity issues prevented Sanofi from marketing Fluzone HD outside of the US, but after investing in increasing capacity, the company decided to market the vaccine in additional regions including Europe, posing a significant threat to Fluad’s European dominance of the elderly segment. Despite Fluad possessing first-to-market advantage in Europe, Fluzone HD captured substantial market share in the 2021/22 influenza season, which was primarily driven by preferential recommendations in both France and Germany (approximately three out of every four elderly individuals in Germany received Fluzone HD). On the other hand, only Fluad was reimbursed in the UK, while Spain and Italy did not state a preference, allowing Fluad to hold on to the bulk of its market share. 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 and conversely for Sanofi to capture more 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-19 vaccine, NVX-CoV2373, and investigation of the combination of both assets. Should Novavax submit a regulatory filing in late 2022, assuming a positive response from the FDA, NanoFlu could launch in time for the 2023/24 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, Datamonitor Healthcare expects NanoFlu to 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. With the commercialization of NanoFlu delayed as Novavax seeks a partner, the company is also exploring other routes including a dual combination vaccine, qNIV/CoV2373, combining NanoFlu with its own COVID-19 vaccine. A dual combination vaccine against influenza and SARS-CoV-2 has a clear logistical advantage by halving appointment numbers, thus reducing the strain of vaccination on healthcare systems.
• With the COVID-19 pandemic drawing attention to the need for routine respiratory vaccination, there is a high demand for pan-respiratory vaccines combining vaccination for influenza, RSV, and COVID-19. A pan-respiratory vaccine would have clear benefits to healthcare systems, eliminating the logistical burden of delivering three standalone vaccines annually. Moreover, discussions with KOLs indicate that vaccine coverage would be expected to be considerably higher than would be achieved for standalone vaccination of influenza or RSV, and, to a lesser extent, COVID-19. Based on current timelines, pan-respiratory vaccines will not enter the market until 2025 at the earliest, with Novavax’s qNIV/CoV2373 being the most advanced asset. Moderna and Pfizer have also stated their interest in developing combination vaccines, but their assets are still in preclinical development. If influenza vaccines prove to be amenable to vaccine cocktails, standalone vaccines may become commercially unviable in the long term unless they have a significant differentiating feature.
• At present, influenza vaccines have shown only moderate efficacy, in the range of 40–60% between seasons. Thus, there is a high unmet need to develop more efficacious vaccines. mRNA vaccines from Moderna, Pfizer/BioNTech, and Translate Bio/Sanofi have entered the clinical pipeline and are the frontrunners in a wave of mRNA vaccines flooding the early pipeline. Additionally, Pfizer/BioNTech, CSL Seqirus, and Arcturus Therapeutics are developing novel self-amplifying RNA (saRNA) vaccines, with Pfizer/BioNTech’s candidate reaching Phase I trials, while the latter two vaccines are in preclinical development. In a preclinical study, Pfizer’s mRNA influenza vaccine achieved higher neutralizing antibody (NAb) titers than comparator trivalent Fluad in mouse models, initially hinting that the vaccine class could offer higher protective efficacy than the current standard-of-care vaccines.
• In contrast to Pfizer’s mRNA vaccine, Moderna’s mRNA-1010 failed to show superior immunogenicity over Fluzone HD. While non-inferior immunogenicity and efficacy will be sufficient for approval, uptake in the lucrative elderly segment will likely require any new entrants to show improvements over well-established market leaders Fluad and Fluzone HD. Given that NAb titers are not strictly indicative of vaccine efficacy, few conclusions can be drawn on the prospects of mRNA vaccines.
• 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 a pivotal Phase III trial. With very limited funding available, BiondVax decided to shelve M-001 while it tries to identify new pipeline assets in the broader infectious disease space, and Datamonitor Healthcare therefore believes that 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, meaning that the earliest a universal vaccine will reach the market is 2024.