Influenza future or investigational therapies

This microchapter covers antiviral agents and vaccines in development or under investigation that are not yet FDA-approved for routine clinical use. For currently approved antivirals, see Medical Therapy. For currently licensed vaccines, see Primary Prevention.

Only three antiviral mechanistic classes are currently marketed for influenza:

• M2 ion-channel inhibitors (amantadine, rimantadine) — no longer recommended due to near-universal resistance among circulating strains.^[1]
• Neuraminidase inhibitors (NAIs) — oseltamivir, zanamivir, peramivir, and laninamivir (the latter approved in Japan).^[1]
• Cap-dependent endonuclease inhibitor — baloxavir marboxil, which targets the PA subunit of the viral polymerase complex.^[1]

Global surveillance data from WHO GISRS (2020–2023) indicate that the great majority of seasonal and zoonotic influenza viruses remain susceptible to both NAIs and baloxavir.^[2] Reduced-inhibition frequencies are low but require ongoing monitoring, particularly for baloxavir resistance markers (PA-I38T/M/L).^[2]

Agents targeting the influenza RNA-dependent RNA polymerase complex (comprising PA, PB1, and PB2 subunits) are among the most promising investigational classes.^[3]

• Onradivir (ZSP-1273) — a first-in-class PB2 inhibitor with activity restricted to influenza A. In a phase 2 randomized controlled trial, onradivir 600 mg once daily demonstrated faster symptom recovery than placebo, with a strong antipyretic effect and good safety profile.^[3] The pivotal phase 3 trial (NCT04683406), reported in 2025, demonstrated a stronger antiviral effect than oseltamivir and a time-to- alleviation-of-symptoms (TTAS) difference versus placebo of −24.52 hours.^[4]
• Pimodivir (JNJ-63623872/VX-787) — another PB2 inhibitor with activity restricted to influenza A. Although it showed antiviral efficacy alone and in combination with oseltamivir, development was discontinued after phase 3 trials demonstrated futility.^[3]
• Favipiravir (T-705) — a PB1/RdRp inhibitor approved in Japan for novel or re-emergent influenza. Clinical trial results in uncomplicated influenza have been inconsistent, and teratogenicity limits its use. Favipiravir is not FDA-approved.^[1][3]

• Umifenovir (arbidol) — approved in Russia and China for influenza treatment. A 2025 network meta-analysis in JAMA Internal Medicine suggested potential symptom duration reduction (mean difference −1.10 days, low certainty), but umifenovir is not approved in the US or EU.^[5][3]

• Laninamivir — a single-inhalation, long-acting NAI approved in Japan but not in the US.^[1]
• Intravenous zanamivir — received European Union marketing authorization in 2019 for severe or resistant influenza, but it is not FDA-approved.^[1]

• Suraxavir marboxil and ZX-7101A are baloxavir-class successors in clinical development, designed to improve upon baloxavir’s resistance profile. These agents are mentioned here for context alongside baloxavir resistance considerations.^[6]

• CD388 — a long-acting zanamivir–Fc conjugate that provides strain-agnostic, single-subcutaneous-dose prophylaxis and treatment. In the phase 2b NAVIGATE trial of unvaccinated adults, CD388 achieved approximately 76% reduction in laboratory-confirmed influenza across a full season. It is now being studied in high-risk and immunocompromised outpatients (NCT07159763).^[7][8] This is arguably the most clinically important novel agent in development.
• VNT-101 — an orally bioavailable nucleoprotein (NP)-oligomerization inhibitor with activity against oseltamivir- and baloxavir-resistant virus, as well as against H5N1 and H7N9 strains. It represents a distinct mechanistic class from currently marketed agents.^[9]

• The FLAGSTONE phase 3 randomized controlled trial evaluated the addition of baloxavir to standard-of-care NAI therapy in hospitalized patients with severe influenza. The combination resulted in more rapid viral clearance but no superior clinical outcome compared with NAI alone. Routine combination therapy is therefore not indicated.^[10]
• Combination therapy in severely immunocompromised patients to suppress resistance emergence remains a plausible but unproven strategy; no randomized controlled trial data exist.^[1]

Monoclonal antibodies targeting conserved hemagglutinin epitopes and other immunotherapeutics remain under early investigation.^[1]

The AD ASTRA head-to-head antiviral platform trial (2026) directly compared baloxavir, favipiravir, and oseltamivir in patients with influenza. Baloxavir demonstrated the greatest in vivo antiviral efficacy, but none of the agents clearly shortened time to complete symptom resolution—highlighting the distinction between virologic and clinical endpoints.^[11]

The central goal of next-generation influenza vaccine development is a broadly protective or “universal” vaccine that provides durable, cross-strain protection without the need for annual reformulation.^[1][12]

mRNA-based platforms are now the predominant next-generation vaccine approach. Multiple candidates are in development to improve seasonal protection, combine with other respiratory virus vaccines (e.g., mRNA COVID-influenza combinations), and target conserved antigens. Most current phase 3 next-generation candidates are mRNA-based.^[13][14]

mRNA technology offers several advantages:

• Rapid strain updating capabilities
• High-valent formulations
• Targeting of conserved internal proteins
• In a ferret model, a T-cell–inducing mRNA candidate encoding conserved NP/M1/PB1 boosted broadly reactive T cells and reduced heterosubtypic (H7N9) disease.^[14]

Additional strategies under investigation include:^[1][12]

• HA-stem–directed antibodies
• Conserved-epitope and nucleoprotein/matrix (CTL-based) targets
• Standardized neuraminidase content in vaccines
• Adjuvanted nanoparticle vaccines for older adults

While not “investigational,” these licensed platforms are important context for understanding the evolution away from egg-based manufacturing, which can reduce effectiveness due to egg-adaptive HA mutations, particularly against A/H3N2.

• Cell-based vaccines (MDCK) — US-licensed since 2012. A meta-analysis of 18 observational studies found a relative vaccine effectiveness of 8.4% (95% CI 6.5–10.2) for cell-grown versus egg-grown quadrivalent vaccine, with greater benefit in seasons with egg-adaptation antigenic mismatch.^[15][16]
• Recombinant HA vaccine (RIV4) — baculovirus/Sf9 expression system, US-licensed since 2013. Contains 3× the HA content and is genetically identical to the selected strain. In a large study of adults aged 18–64, recombinant vaccine provided relatively better protection than standard-dose egg-based vaccine.^[17]

Figure 1 provides a schematic overview of influenza vaccine platforms from traditional inactivated/live-attenuated approaches through recombinant, VLP, viral-vector, DNA, mRNA, and nanoparticle/multi-epitope strategies.

The 2024 WHO influenza guideline, summarized in the BMJ (2026), incorporates new randomized controlled trial evidence and conditionally recommends baloxavir within 48 hours for patients at high risk of progression, and oseltamivir for severe illness. This reflects the evolving positioning of the newest approved agent, not any investigational drug.^[18]

A 2025 network meta-analysis in JAMA Internal Medicine (73 RCTs, 34,332 patients, GRADE) found:^[5]

• Baloxavir probably reduces symptom duration (mean difference −1.02 days, moderate certainty) and may reduce hospitalization in high-risk patients (low certainty) without increased adverse events, but may cause resistance in approximately 10% of treated patients.
• All antiviral agents had little or no effect on mortality (high certainty).

• Baloxavir resistance — PA-I38T/M/L substitutions emerge readily (approximately 10% of treated patients, higher in children and A/H3N2; up to 3.3% surveillance rate in Japan 2022–2023), with documented household transmission. This raises questions about widespread monotherapy use.^[1][2]
• Role of combination therapy to suppress resistance in immunocompromised hosts remains unresolved, with no randomized controlled trial data.^[1]
• No fully-enrolled placebo-controlled RCT of any antiviral exists for hospitalized or severe influenza; benefit rests on observational data — a persistent evidence gap.^[1]
• “Universal” vaccine definition, correlates of protection, and integration into existing strain-selection and manufacturing systems remain unsettled; most candidates remain early-phase.^[1][12][13]

• Baloxavir (PA inhibitor) is a single oral dose, has greater efficacy against influenza B than oseltamivir, and reduces viral load faster than NAIs.^[1][19][20]
• CD388 (long-acting zanamivir–Fc conjugate) is the most advanced novel mechanism in clinical development, with phase 2b data showing ~76% reduction in laboratory-confirmed influenza over a full season.^[7][8]
• Recombinant (RIV4) and cell-based vaccines avoid egg-adaptive mutations; consider them when A/H3N2 egg-mismatch is a concern.^[15][17]

• Calling peramivir or baloxavir “investigational” — both are FDA-approved.^[1]
• Adding baloxavir to an NAI for hospitalized severe influenza expecting better clinical outcomes — FLAGSTONE showed no clinical benefit.^[10]
• Using baloxavir in pregnancy — CDC explicitly does not recommend baloxavir in pregnancy or breastfeeding, nor in hospitalized patients, severely immunocompromised patients, or those with complicated/progressive illness.^[21][1]
• Assuming favipiravir or umifenovir are available or endorsed in the US or EU — they are not FDA/EMA-approved.^[1][3]