As respiratory vaccines continue to place a substantial strain on healthcare systems worldwide, vaccine development has entered a new era.
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This article examines the history of respiratory virus vaccines, how modified mRNA (modRNA) technology may overcome the limitations of existing vaccines, and the development of universal vaccines for influenza, COVID-19, and other viruses.
In addition, the paper outlines the crucial role human challenge trials will play in accelerating vaccine development and producing high-quality data. With its advanced facilities, profound scientific expertise, and a strong track record, hVIVO is uniquely positioned to support customers in navigating this new landscape and efficiently deliver cutting-edge vaccines to market.
1. modRNA vaccines are redefining respiratory virus prevention
A new era of vaccine development has been ushered in thanks to the success of modRNA vaccines during the COVID-19 pandemic.
Their capability for rapid design to target emerging strains, scalable manufacturing methods, and potential to enable universal protection (e.g., against all influenza strains) position them as a transformative platform for preventing respiratory viruses.
2. Human challenge trials can accelerate vaccine development
Conventional vaccine field trials are slow, expensive, and frequently produce low-quality data. In contrast, human challenge trials reduce time and expenses while generating robust viral load and symptomology data.
Another key advantage over field trials is the ability to evaluate efficacy against low-circulation virus strains, which frequently lead to seasonal vaccine mismatch and variable effectiveness.
3. hVIVO will be at the forefront of vaccine clinical development
hVIVO is a leader in vaccine and anti-viral clinical development due to its extensive experience and tailored quarantine site. Its human challenge models allow products to "succeed fast or fail fast," substantially minimizing risks and expenses.
Respiratory viruses remain a significant global health threat, challenging both public health systems and vaccine developers. This article examines the changing landscape of respiratory viral infection prevention, including the shortcomings of conventional vaccine platforms and the potential of modified messenger RNA (modRNA) technology.
It also highlights the transformative impact of human challenge trials and explains how hVIVO’s specialist capabilities and expanded infrastructure position it at the forefront of vaccine development by accelerating trial results, generating high-quality data, and minimizing risk and expenses.
The global burden of respiratory viral infection
In 2025, respiratory viruses continued to pose significant challenges to global public health. Their tendency to mutate enables frequent immune evasion and high cross-species and human-human transmissibility which, coupled with their seasonality, has complicated the development of vaccines that provide broad (i.e., covering many or all strains of a virus) and lasting protection.
The need for annual vaccine updates creates a continuous economic burden while vaccine-strain match remains unreliable.
Influenza viruses exemplify these challenges.
Although current vaccines prevent millions of cases each year (around 9.8 million in the United States alone for the 2024/2025 season), influenza causes approximately one billion cases (including three to five million severe cases) of illness and between 290,000 and 650,000 global deaths annually.1,2
Influenza viruses continually evade both acquired and vaccine-induced immunity through antigenic drift and occasional rapid antigenic shift.3 This requires constant surveillance and annual vaccine reformulation to counter prevalent and newly emerging strains.
Seasonal infection patterns, driven by climate, host behavior, and co-circulation with other respiratory pathogens, further complicate prediction and preparedness.4
The World Health Organization (WHO) Global Influenza Surveillance and Response System (GISRS) was founded in 1952 and now operates with networks across 130 WHO member states.5 GISRS holds biannual meetings, typically in February and September for the Northern and Southern hemispheres, respectively.
During these meetings, experts review epidemiological data, genetic and antigenic properties, and vaccine effectiveness before providing recommendations for strains to include in upcoming seasonal vaccines.
In February 2025, the latest recommendations for the Northern hemisphere were released.6 Regulatory authorities, including the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), can modify which strains are included in their region, according to local epidemiological data.
Despite seasonal adjustments, emerging mutations frequently result in vaccine mismatch, leading to significant variability in influenza vaccine effectiveness by year and by region . Since the 2004/2005 season, influenza vaccine efficacy estimates in the United States have ranged from 10 % to 60 %.7
History of respiratory virus vaccines
Until the recent emergence of modRNA vaccines, most respiratory virus vaccines have been either live attenuated vaccines (LAVs), where a live virus with reduced virulence is used to stimulate an immune response, or inactivated virus vaccines.
LAVs have been used since World War II and remain common today due to the stronger and more durable immunity they induce. More recently, intranasal administration (e.g., AstraZeneca’s “Fluenz” influenza vaccine) has proven extremely useful for vaccinating children. Disadvantages of LAVs include contraindications in pregnant and immunocompromised individuals, and the risk of mutations into more virulent strains.
Inactivated virus vaccines involve administering all or part (e.g., split virions) of an inactivated or dead virus. The antigens from the inactivated virus cause a different and potentially weaker immune response than LAVs, often requiring several doses or the addition of adjuvants. Inactivated virus vaccines, including Sanofi’s quadrivalent influenza vaccine, are still used today due to their strong safety profile.
Both LAVs and inactivated virus vaccines work by introducing all or part of a virus to stimulate an immune response. Historically, these vaccines were manufactured in egg-based production procedures, which carried the risk of supply chain issues. Egg-adaptation changes to the viruses are also known to increase vaccine mismatch and reduce effectiveness.8
To address these challenges, cell-based (i.e., grown in a cell culture) vaccines emerged, offering faster and larger-scale manufacturing methods and allowing more efficient responses to emerging strains and potential pandemics.
Genetically engineered recombinant influenza vaccines entered the market in 2013. These vaccines are produced by synthesizing synthetic viral DNA (in the case of influenza, the DNA encoding the haemaggluttinin [HA] protein) and inserting (recombining) it into the genome of the host virus. The host is then cultured to generate large quantities of the target protein, which is purified and formulated into the vaccine. Recombinant vaccines offer additional production efficiencies and have been demonstrated to trigger stronger immune responses than both egg- and cell-based vaccines.9
The arrival of modRNA vaccines
modRNA technology offers a significant opportunity for the development of new vaccines against influenza and other respiratory viruses. In contrast to conventional vaccines, which introduce viral antigens directly to stimulate an immune response, synthetic modRNA is delivered and then translated by the host cells to produce the viral antigen(s) encoded by the modRNA. The antigen(s) produced may then stimulate both humoral and cell-mediated immune responses.
Although modRNA has been studied as a therapeutic platform since the late 1980s, early development was limited by poor stability and undesirable innate immunogenicity through the activation of toll-like receptors.10
Breakthroughs in nucleoside modification in the early 2000s, (specifically, the development of pseudouridine, an analogue of uridine) enhanced modRNA stability and decreased these unwanted immunogenic effects.11
The COVID-19 pandemic dramatically accelerated the approval of the first modRNA vaccines, highlighting their distinct advantages over conventional vaccine platforms: rapid development and scalable manufacturing. Once SARS-CoV-2 had been sequenced, researchers already working on modRNA rapidly designed SARS-CoV-2 vaccine candidates, and clinical trials began within months.
Within only one year of the virus’ identification, the FDA/EMA authorized the emergency/conditional use of two mRNA vaccines (developed by BioNTech/Pfizer and Moderna). The cell-free production process of modRNA vaccines could be rapidly scaled up to address the huge demand created by the pandemic.
Initially, the modRNA vaccines, based on wild-type SARS-CoV-2 (Wuhan-Hu-1), demonstrated approximately 95 % efficacy in reducing symptomatic COVID-19.12 As novel SARS-CoV-2 strains emerged, protection against severe disease remained high; however, overall vaccine efficacy began to decline.
To counter dominant strains, formulations have undergone regular updates. The WHO Technical Advisory Group on COVID-19 Vaccine Composition has recommended both bivalent and monovalent vaccines in the years since.
The future of respiratory virus vaccines
The remarkable success of modRNA vaccines against SARS-CoV-2, prompted the rapid development of other modRNA vaccines. Last year, the FDA approved mRESVIA, a modRNA vaccine encoding the respiratory syncytial virus [RSV] fusion [F] protein, for use in adults aged 60 years and older. modRNA vaccines for cytomegalovirus and Epstein-Barr virus are also in the early stages of development.
modRNA technology offers an opportunity for the development of universal vaccines (i.e., a vaccine that protects against all strains of a virus) by targeting conserved antigens (e.g., the HA stem, instead of the variable head). Universal modRNA vaccines for influenza and coronavirus, as well as a combined influenza and SARS-CoV-2 candidate, are currently under investigation in Phase 3 studies, with hopes for approval next year.
If universal modRNA vaccines prove effective against influenza and coronavirus variants, the 2020s could be defined as a new era in vaccine development. Eliminating the need for seasonal vaccine reformation, combined with the inherent production advantages of modRNA vaccines, could significantly reduce the economic burden of these diseases.
Universal vaccines have the potential to eradicate certain diseases in humans or at least eliminate their incidence in vaccinated populations. However, modRNA vaccines are not without drawbacks. Challenges include increased reactogenicity and shorter immunity duration compared with other vaccine types. Current ultra-cold storage requirements complicate distribution; manufacturers will no doubt concentrate on enhancing storage conditions to enable easier, cheaper, and more ubiquitous distribution.
Accelerating vaccine development with human challenge models
At this pivotal time for vaccines, clinical development strategies must be optimized and up to date with the latest advances. Conventional vaccine field trials, which involve vaccinating large cohorts of participants and observing them over extended periods, can be an expensive and inefficient gamble for vaccine candidates.
These studies also suffer from low-quality data outputs (e.g., using proxy endpoints of influenza-like illness rather than more specific and comprehensive viral load assessments). Field trials struggle to evaluate efficacy against low-circulation strains, and the seasonality of respiratory viruses prevents adequate assessment of efficacy before vaccines are deployed.
Human challenge trials (HCTs), also known as controlled human infection models (CHIMs), involve the deliberate exposure of participants to the pathogen being studied with or without a test treatment or vaccine. Participants are monitored in a controlled environment during the predicted course of disease to evaluate infection rates, viral load, and symptomology.
The origins of HCTs date back to 1796, when Edward Jenner inoculated a young patient with cowpox. The patient later demonstrated immunity to smallpox, which causes more severe disease than cowpox, and the experiment ultimately laid the foundation for the concept of vaccines.
Since then, HCTs have advanced substantially, adapting to contemporary ethical standards and regulations. They have contributed to the development of vaccines for diseases such as influenza, dengue, norovirus, malaria, cholera, typhoid, and RSV. HCTs deliver rapid and more comprehensive results.
By controlling study conditions, variability is reduced, and interference from other pathogens is avoided, enabling more accurate virological and immunological assessments. This allows for smaller sample sizes compared to conventional field studies, reducing both the cost and risk of early-stage vaccine development.
hVIVO's human challenge trials
hVIVO has an unmatched history in conducting HCTs. After conducting its first HCT in 2001, the company opened its first dedicated quarantine facility and associated laboratories in 2011. Renewed interest in HCTs during the COVID-19 pandemic led the company to expand its facilities in 2021, including an HCT in 36 participants to characterize SARS-CoV-2.
Overall, hVIVO has challenged more than 5,000 participants with respiratory viruses and other pathogens. The company has established human challenge models for contemporaneous influenza A and B, RSV A and B, hMPV, human rhinovirus, and SARS-CoV-2. Its integrated specialist virology lab has validated qualitative and quantitative assays for each of these viruses, enabling seamless operations throughout their studies.
Last year, recent growth resulted in the opening of a flagship quarantine and lab site in Canary Wharf, London. The 50-bed quarantine site is certified to handle pathogens as high as biosafety level 3 (BSL3) and can support multiple pathogens simultaneously. hVIVO has the facilities and expertise to lead the way in this new era of vaccine innovation.
HCTs conducted by hVIVO can generate high-quality data efficiently, enabling vaccine and therapeutic candidates to succeed fast or fail fast. In addition, the company’s timely results could support innovations in seasonal vaccine assessment and subsequent development. hVIVO can develop models and assays for rare virus strains, which will be indispensable for the evaluation and approval of universal vaccines.
hVIVO’s expanded clinical trial and consultancy offering
Canary Wharf’s on-site pharmacy, IMP facilities, and outpatient unit, together with hVIVO’s dedicated project management and clinical teams, are primed and ready to accelerate vaccine and antiviral development. hVIVO’s comprehensive participant database supports the rapid recruitment of healthy participants, including older populations, as well as patients with asthma or COPD.
In 2020, Venn Life Sciences, a specialist consultancy in early-phase clinical development, joined the hVIVO group (formerly Open Orphan). Venn’s highly respected team of consultants has experience covering preclinical development, CMC, pharmacokinetics, statistics and methodology, data management, medical writing, quality assurance, and regulatory affairs. Close collaboration between Venn and hVIVO’s clinical site teams ensures that clinical trials are executed to the highest scientific and regulatory standards.
In January 2025, hVIVO acquired CRS, an early-phase clinical research organization headquartered in Germany. This acquisition allowed hVIVO to use two clinical trial units and accompanying expert teams to expand its overall site offering into the EU. The sites specialize in first-in-human studies and complex pharmacokinetic and pharmacodynamic studies in patients with renal or hepatic impairment.
hVIVO’s presence in Germany will enable clients to benefit from the recent proposals by the German Federal Ministry of Health for new Standard Contractual Clauses (SCs). These SCs will substantially reduce Clinical Trial Agreement (CTA) review times once finalized.
With a cutting-edge quarantine site, advanced laboratories, and an expanded site and service offerings, hVIVO is undoubtedly well-positioned to support the development of vaccines and antiviral therapeutics. Experts provide guidance throughout the entire product lifecycle, from feasibility through to the full execution of Phase 1 to 3 trials.
While human challenge models can enhance the efficiency of the key early phases in vaccine programs, hVIVO’s expanded capacity can be utilized to carry out field trials, which will remain essential for generating longer-term and robust safety data and for pathogens unsuitable for challenge trials.
References and further reading:
- Centers for Disease Control and Prevention (CDC) (2024). Flu Burden Prevented by Vaccination. (online) Flu Burden. Available at: https://www.cdc.gov/flu-burden/php/data-vis-vac/index.html.
- World Health Organization: WHO (2018). Influenza (Seasonal). (online) WHO. Available at: https://www.who.int/news-room/fact-sheets/detail/influenza-%28seasonal%29.
- Centers for Disease Control and Prevention (CDC) (2024). How Flu Viruses Can Change: ‘Drift’ and ‘Shift’. (online) Influenza (Flu). Available at: https://www.cdc.gov/flu/php/viruses/change.html.
- Lofgren, E., et al. (2007). Influenza Seasonality: Underlying Causes and Modeling Theories. Journal of Virology, (online) 81(11), pp.5429–5436. DOI: 10.1128/JVI.01680-06. https://journals.asm.org/doi/full/10.1128/jvi.01680-06.
- World Health Organization (2024). Global Influenza Surveillance and Response System (GISRS). (online) WHO. Available at: https://www.who.int/initiatives/global-influenza-surveillance-and-response-system.
- World Health Organization (WHO). Recommended composition of influenza virus vaccines for use in the 2025-2026 northern hemisphere influenza season. (online) WHO. Available at: https://www.who.int/publications/m/item/recommended-composition-of-influenza-virus-vaccines-for-use-in-the-2025-2026-nh-influenza-season.
- Centers for Disease Control and Prevention (CDC) (2020). Past Seasons Vaccine Effectiveness Estimates | CDC. (online) Available at: https://www.cdc.gov/flu-vaccines-work/php/effectiveness-studies/past-seasons-estimates.html.
- Ortiz, R., et al. (2021). Estimation of Reduction in Influenza Vaccine Effectiveness Due to Egg-Adaptation Changes - Systematic Literature Review and Expert Consensus. Vaccines, (online) 9(11), pp.1255–1255. DOI: 10.3390/vaccines9111255. https://www.mdpi.com/2076-393X/9/11/1255.
- Liu, F., et al. (2024). Redirecting antibody responses from egg-adapted epitopes following repeat vaccination with recombinant or cell culture-based versus egg-based influenza vaccines. Nature Communications, (online) 15(1). DOI: 10.1038/s41467-023-44551-x. https://www.nature.com/articles/s41467-023-44551-x.
- Karikó, K., et al. (2004). mRNA Is an Endogenous Ligand for Toll-like Receptor 3. Journal of Biological Chemistry, 279(13), pp.12542–12550. DOI: 10.1074/jbc.m310175200. https://www.sciencedirect.com/science/article/pii/S0021925819641931.
- Karikó, K., et al. (2005). Suppression of RNA Recognition by Toll-like Receptors: The Impact of Nucleoside Modification and the Evolutionary Origin of RNA. Immunity, (online) 23(2), pp.165–175. DOI: 10.1016/j.immuni.2005.06.008. https://www.cell.com/immunity/fulltext/S1074-7613(05)00211-6.
- Waltz, E. (2022). COVID vaccines: head-to-head comparison reveals how they stack up. Nature. DOI: 10.1038/d41586-022-00885-y. https://www.nature.com/articles/d41586-022-00885-y
About hVIVO
hVIVO is a full-service early phase CRO offering end-to-end drug development services from preclinical consultancy through to Phase III clinical trials, including world-leading end-to-end human challenge trials services. With decades of experience in rapidly delivering data for our global client base, our team brings together strategic insight and operational expertise to deliver a variety of clinical study types across multiple locations.
To support rapid study start-up and reliable delivery, our dedicated recruitment teams in Germany and the UK provide direct access to both healthy volunteers and patient populations. This is complemented by our integrated drug development consultancy, as well as our infectious disease and immunology laboratories and biobanking services.
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