Writer: Meghan Diefenbacher
Editor: Pari Dhayagude
The influenza virus is a respiratory pathogen that remains a significant global public health burden. Seasonal epidemics of influenza cause approximately 3-5 million cases of severe illness and 290,000-650,000 respiratory deaths worldwide.1 Although the number of seasonal influenza virus infections initially decreased during the SARS-CoV-2 pandemic, they have rebounded to pre-pandemic levels,2,3 and the current 2025-2026 season in the United States has been especially severe with over 120,000 hospitalizations, 5,000 deaths, and case numbers continuing to rise.4 Compounding the impact of seasonal influenza outbreaks is the risk of pandemics originating from zoonotic (animal-borne) influenza strains.5,6 Over the past 100 years there have been four major influenza virus pandemics responsible for millions of deaths.5 Additionally, zoonotic influenza strains like H5N1 have continued to circulate and cause mass mortality in wild bird and mammal populations, domestic poultry and cattle, and sporadic high mortality infections in humans exposed to infected animals.7,8
To mitigate the threats posed by both seasonal and pandemic influenza virus outbreaks, the development of therapeutics (drugs and vaccines) that are broadly protective against highly diverse influenza virus strains and provide long-lasting protection is urgently needed. Current vaccines are only effective against seasonal influenza strains and must be updated annually due to the rapid evolution of influenza viruses.9 Several FDA approved antivirals are available to treat influenza virus infections, however, they are only effective during the early stages of infection, and mutations conferring resistance to these antivirals have been documented in both laboratory and clinical settings.10 Addressing the concerns regarding the limited breadth and short-term efficacy of current influenza virus therapeutics, Cidara Therapeutics, recently acquired by Merck, developed a novel long-acting and broadly protective anti-influenza antiviral drug called CD388 which has exhibited efficacy in recent early stage clinical trials.11
What is the influenza virus and how does it cause disease?
Influenza viruses are members of the Orthomyxoviridae family, distinguished by their segmented, negative-sense RNA genomes.12 Influenza viruses are divided into four types- A (IAV), B (IBV), C (ICV), and D (IDV).12 Only IAV, IBV, and ICV infect humans with IAV and IBV being responsible for seasonal influenza epidemics and only IAV causing past influenza pandemic outbreaks.12
Influenza Virus Transmission, Symptoms, and Disease Severity
Influenza viruses are primarily transmitted to uninfected people via inhalation of respiratory droplets released into the air after an infected person coughs or sneezes, or via contact with contaminated surfaces and then touching the eyes, nose, or mouth.1 Symptoms begin to develop between 1 and 4 days post-infection, and uncomplicated cases of influenza last around one week.1 Infections are primarily characterized by the sudden onset of fever and upper respiratory tract symptoms such as dry cough, sore throat, and a runny nose.1 Infection can also be accompanied by other symptoms such as headaches, malaise (feeling unwell), and muscle and joint pain.1 Although a majority of infections resolve within a week, people with pre-existing conditions (obesity, asthma, diabetes, heart disease etc.), pregnant women, the very young (<5 years old) and elderly (>65 years old), and those who are immunocompromised can develop additional complications such as bronchitis, sinus infections, viral or secondary bacterial pneumonia, exacerbation of symptoms related to pre-existing conditions, respiratory failure, and death.1,12
Influenza Virus Particle Structure and Classification
IAV and IBV particles consist of the viral genetic material enclosed within an outer lipid envelope supported underneath by a layer of the viral matrix (M1) protein and studded with the viral surface proteins hemagglutinin (HA), neuraminidase (NA), and M2 (Figure 1).13,14 The viral genetic material is divided into eight RNA segments in the form of ribonucleoprotein complexes (RNP) in which each segment is coated along its length by the viral nucleoprotein (NP) and associated with the viral replicase (PB2, PB1, PA) (Figure 1).13,14 Unlike IBV, which has only two lineages (B/Victoria and B/Yamagata), IAV strains are highly diverse and are further classified into subtypes based on the identity of their HA and NA surface proteins.12,15 There are 18 known HA subtypes and 11 known NA subtypes, and IAV strains are named based on the identities of their HA and NA subtypes (ex. A/HxNy).15
The Surface Proteins HA and NA Play a Critical Role in Influenza Virus Replication
Influenza viruses target host cells by binding to sialic acids (SAs), which are the terminal sugar molecules present within the larger carbohydrate structures attached to cell-membrane associated proteins (glycoproteins) or lipids (glycolipids).16 The binding of HA triggers the uptake of the virus into the cell (endocytosis) where its proteins direct the replication of the viral genetic material and the synthesis of additional viral proteins to form new virus particles (Figure 2).13 The virus particles then bud from the cell surface and are released via the activity of NA, which cleaves the SAs tethering the viral particles to the cell surface (Figure 2).13 The opposing activities of HA and NA need to be balanced to ensure efficient viral replication.17,18 For instance, if HA attachment is more efficient than NA cleavage, the viruses will remain stuck on the cell surface. Conversely, if NA cleavage is more efficient than HA attachment, the SAs will be cleaved, preventing the virus from binding to and entering the host cell. Due to the essential roles of HA and NA in influenza virus attachment/entry, both HA and NA are important targets for influenza vaccine and drug development.
Importance of HA and NA in the Design of Influenza Virus Vaccines and Current Limitations
Vaccination against seasonal influenza viruses remains an essential component of the public health strategy to reduce influenza-related morbidity and mortality.19 Each year, based on the identities of circulating influenza strains, the World Health Organization (WHO) Global Influenza Surveillance and Response System (GISRS) makes recommendations for which strains to include in the vaccine.9,20 Seasonal influenza infections are primarily caused by two IAV subtypes- A(H1N1) & A(H3N2)- and IBV, so vaccine formulations are typically quadrivalent or trivalent, meaning that they contain two IAV strains (one of each A(H1N1) and A(H3N2) subtype), and one or both of the IBV strains of the Victoria (B/Victoria) or Yamagata (B/Yamagata) lineages.9,20 However, since the SARS-CoV-2 pandemic emerged in 2020, the B/Yamagata strain has not been detected in human populations, so it is now recommended that the vaccines only include IBV strains of the B/Victoria lineage.21 Traditionally, influenza vaccines are made by growing the selected influenza strains in eggs, harvesting the virus-containing fluid, inactivating the viruses, breaking apart the virus particles, and then separating out the viral proteins (antigens).22 The viral antigens in the vaccine stimulate the immune system to produce antibodies primarily against HA, and to a lesser extent NA, to inhibit their activities and prevent virus replication.22–24
While vaccines play an integral role in the public health strategy to mitigate influenza virus epidemics, they exhibit several drawbacks, including limited breadth, requirements for annual updates, and variable efficacy.9,20 Influenza vaccines protect against seasonal influenza viruses but not zoonotic strains, and must be continually updated due to the rapid evolution of influenza viruses, which acquire mutations that render vaccine-induced antibodies ineffective, a process known as antigenic drift.9,20 Additionally, the vaccine efficacy is highly variable (varying from ~19-60% between 2009 and 2025)25 and is influenced by several factors. For instance, there may be a mismatch between the influenza strains selected by WHO GISRS and those that circulate during the season.9,20,26 Additionally, the viruses used in vaccine production can acquire mutations during production, known as egg-adaptive mutations.9,20,26 Vaccine effectiveness is also influenced by variable vaccine uptake rates and individuals’ previous exposure and vaccination histories.26–28 Overall, the development of a universally protective influenza vaccine that does not require annual updates remains a significant public health challenge and opens the door to alternative approaches to provide long-lasting and broad protection against influenza virus infections.
Current Benefits and Drawbacks of Contemporary NA Inhibitors for the Treatment of Influenza Infections
Out of the four FDA-approved antiviral drugs available to treat influenza virus infections, a majority (3/4) are NA inhibitors (NAIs): Zanamivir (Relenza®), Oseltamivir (Tamiflu®), and Peramivir (Rapibav®).29 NA is a valuable therapeutic target not only because of its essential role in the influenza virus replication cycle, but also because the region of the NA protein that binds to and cleaves the SAs (the active site) is highly conserved throughout both IAV and IBV strains, increasing the potential breadth of antiviral activity.30,31 Consequently, most NAIs are designed as SA analogues that bind to the active site in the place of cellular SAs and inhibit the cleavage activity of NA .32,33 The lack of NA activity prevents virus spread by causing the virus to cluster on the cell surface and get trapped by decoy receptors within the mucus layer of the respiratory tract.30 Of the three NAIs, Oseltamivir is the most commonly used because it is available as an oral pill, whereas Zanamivir and Peramivir must be administered via inhalation and intravenously respectively.32,33 A limitation of these NAIs is that to be effective, they must be administered within 48 hours of symptom onset, making the treatment window very narrow.34 Additionally, NAI resistance mutations, although typically low in prevalence (~1% average), can inhibit the activity of these drugs and have been identified in laboratory settings, circulating strains, and in immunocompromised patients with prolonged influenza infections.35–39 Therefore, it is of interest to develop new NAIs that are long-acting and decrease the likelihood of developing antiviral resistance.
What is the mechanism of action of CD388 against influenza NA and how does it provide broad and long-lasting protection against influenza virus infections?
Cidara Therapeutics’ (acquired by Merck) anti-influenza drug CD388 was developed as part of the company’s Cloudbreak® platform portfolio of drugs. The Cloudbreak® platform drugs are designed as conjugates of small molecule or peptide drugs and antibody fragments (Fc) that exhibit disease-specific, targeted drug activity and can be modified to stimulate the host immune response.40
CD388 contains two major features: an antibody fragment backbone and multiple conjugates of the NAI Zanamivir (Figure 3).41 The antibody fragment backbone serves as the platform for the binding of multiple Zanamivir dimers (groups of two) and is engineered with mutations that increase the stability and overall half-life of CD388 in the body (Figure 3).41
CD388 exerts its antiviral activity through Zanamivir, which prevents NA from cleaving sialic acids and facilitating the release of virus particles from the cell surface (Figure 4).41,42 This prevents the virus from spreading to new tissues by causing the aggregation of virus particles (Figure 4).41 The dimeric nature and presence of multiple copies of Zanamivir in CD388 allow it to inhibit the activity of multiple adjacent NA proteins within a virus particle as well as NA proteins in neighboring viruses, thereby increasing neuraminidase inhibition and causing further virus aggregation (Figures 3,4).41
CD388 exhibits several advantages including broad antiviral activity against influenza strains, a lower likelihood of developing antiviral resistance, and its long-acting antiviral activity. As CD388 contains Zanamivir which already has broad anti-influenza activity due to targeting the highly conserved NA active site, CD388 also exhibits broad antiviral activity against both seasonal and pandemic IAV strains and IBV strains.41 In preclinical studies, CD388 exhibited potent antiviral activity against a diverse panel of IAV and IBV strains in cells and protection against virus replication, weight loss, and disease in mouse models.41 An advantage of CD388 relative to other available NAIs is its low likelihood of developing antiviral resistance, and the maintenance of antiviral activity against influenza strains with NAI resistance mutations.41 For instance, even after multiple rounds of passaging the virus in cells in the presence of CD388, only a few resistance mutations were identified which only marginally increased virus replication in the presence of the drug.41 Additionally, CD388 continued to provide protection against influenza strains with known NAI mutations in mouse models.41 The authors hypothesized that CD388 increased the barrier for antiviral resistance due to its multivalent nature (its ability to bind to and inhibit the activity of multiple NAs simultaneously) which results from the dimerization of the associated Zanamivir and the presence of many Zanamivir dimers throughout the antibody fragment.41,42 Finally, the engineered antibody fragment promotes stability and prolongs antiviral activity in vivo.41 In preclinical studies, the authors found the half-lives of CD388 were 106 hours (~4 days) in mice and 364 hours (~15 days) in cynomolgus macaques.41 Additionally, CD388 was maintained at sufficient levels up to one week post treatment and continued to provide protection against weight loss and death in mouse models.41 The stability of CD388 has the potential to lower the overall number of doses required to provide sufficient protection against influenza virus replication.
The Early Stage NAVIGATE Clinical Trial Demonstrates the Efficacy of CD388 as a Long-Acting Antiviral for the Prevention of Seasonal Influenza Virus Infections
NAVIGATE Clinical Trial Results
In June 2025, encouraging results were released from the Phase 2b randomized, double-blind, and placebo controlled NAVIGATE clinical trial (NCT06609460)43 which evaluated the safety, tolerability, and efficacy of CD388 for the prevention seasonal influenza infections in healthy, unvaccinated adults (18-64 years old).11,43 The participants received subcutaneous (SC) doses of either 450mg, 300mg, or 150mg of CD388 or the placebo and were evaluated for influenza-like illness (ILI) as the primary endpoint and presence of fever (37.8°C or 37.2°C) as the secondary endpoint after 24 weeks.11,43 ILI was defined as a positive influenza RT-PCR test from a nasal swab sample, the new onset of a fever (>38°C), and the new onset of at least two respiratory symptoms (nasal congestion, sore throat, cough) or one respiratory symptom and one systemic symptom (headache, feeling feverish, body aches/pains, fatigue).11,43 After 24 weeks, the 450mg, 300mg, and 150mg doses of CD388 were 76.1%, 61.3%, and 57.7% effective at preventing ILI respectively.11 Additionally, the 450mg, 300mg, and 150mg doses of CD388 were 76.1%, 55.3%, and 54.7% effective at preventing new onset fever >37.8°C respectively, and 71.1%, 49.6%, and 46.5% effective at preventing new onset fever >37.2°C respectively.11 In all groups CD388 was well tolerated and treatment did not lead to any adverse events.11 The finding that a single dose of CD388 protected against ILI and fever for 24 weeks is encouraging as it presents CD388 as an additional option alongside vaccines for long-acting, seasonal protection against influenza.
Upcoming Clinical Trials for CD388 and Future Directions
ANCHOR Clinical Trial
The NAVIGATE clinical trial demonstrated that CD388 was effective at preventing ILI in unvaccinated, healthy adults, so the Phase 3 ANCHOR clinical trial (NCT07159763) was initiated to determine whether CD388 could also benefit patients with pre-existing conditions who are at the highest risk of developing complications from influenza virus infections.44 The participants will receive 450mg of CD388 or a placebo and will be evaluated for ILI from 8 days post-treatment through 24 weeks post-treatment.44 The study will also evaluate the safety and tolerability of CD388, measure plasma concentrations of CD388 over time, and determine whether any anti-CD388 antibodies that may interfere with its activity are produced during the study.44 If CD388 also provides significant protection against ILI in patients with high risk of developing complications from influenza virus infections, it could significantly reduce the burden of influenza-related hospitalizations and deaths in these groups. Furthermore, it would offer an additional option for patients who cannot be vaccinated or tolerate other anti-influenza antiviral therapies.
Future Directions for Influenza Therapeutic Development
Due to its long-acting nature and efficacy against diverse influenza virus strains, CD388 fills a unique niche in between traditional antivirals and vaccines with the potential to provide season-long protection against the rapidly evolving seasonal influenza strains and potentially pandemic influenza strains. Alongside the development of CD388, influenza vaccine and antiviral development continue to progress. Novel vaccine production platforms (mRNA vaccines, virus-like particles, nanoparticles etc.) have the potential to increase production efficiency, decrease the number of mutations introduced during the production process, and allow for the incorporation and targeting of novel, more highly conserved viral antigens (M1, M2, NP) or multiple HA and NA antigens from diverse influenza strains to develop a more universally protective influenza vaccine.9,45 In the influenza antiviral space, novel small molecule antivirals and monoclonal antibodies that target more conserved regions of HA and NA, small molecules that inhibit the activity of more highly conserved viral proteins (M2, viral replicase (PB2, PB1, PA), and NP), antiviral therapies combining antivirals targeting different viral proteins, and antivirals targeting host factors required for viral replication have the potential to increase the breadth of antiviral activity and decrease the risk of antiviral resistance.46 Complementing next-generation influenza vaccines and antivirals, CD388, with its long-acting and broadly protective anti-influenza activity, serves as an additional tool in the influenza virus therapeutic arsenal to help mitigate the significant public health burden of both seasonal and future pandemic influenza virus outbreaks.
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