Executive Summary
As respiratory vaccines continue to impose significant burdens on healthcare systems around the world, vaccine development has entered a transformative era. This white paper explores the history of respiratory virus vaccines, how modified mRNA (modRNA) technology could resolve the problems seen with currently available vaccines, and the development of universal vaccines for the prevention of influenza, COVID-19, and other viruses.
The paper also highlights the critical role of human challenge trials will play in accelerating vaccine development and generating high-quality data. With its state-of-the-art facilities, deep scientific expertise, and proven track record, hVIVO is uniquely positioned to support clients in navigating this new landscape and bringing innovative vaccines to market efficiently.
1. modRNA Vaccines Are Redefining Respiratory Virus Prevention
The success of modRNA vaccines during the COVID-19 pandemic has ushered in a new era in vaccine development. Their ability to be rapidly designed to target new strains, scalable production techniques, and potential for universal protection (e.g., against all influenza strains) position them as a transformative platform for respiratory virus prevention.
2. Human Challenge Trials Can Accelerate Vaccine Development
Traditional vaccine field trials are slow, costly, and often yield poor quality data. Human challenge trials save time and money whilst providing robust viral load and symptomology data. Another distinct advantage over field trials is the ability to assess efficacy against low-circulation virus strains, which can often lead to seasonal vaccine mismatch and variable efficacy.
3. hVIVO Will be at the Forefront of Vaccine Clinical Development
hVIVO’s extensive experience and bespoke quarantine facility have made it a leader in vaccine and anti-viral clinical development. Their human challenge models enable products to "succeed fast or fail fast," significantly reducing risks and costs.
Respiratory viruses continue to pose a major global health threat, challenging public health systems and vaccine developers alike. This white paper will explore the evolving landscape of respiratory viral infection prevention, including the limitations of traditional vaccine platforms and the promise of modified messenger RNA (modRNA) technology. It will also outline the transformative role of human challenge trials and how hVIVO’s specialist capabilities and expanded infrastructure place it at the forefront of vaccine development by accelerating trial results, providing high-quality data, and reducing risks and costs.
Respiratory viruses remain a significant global public health challenge in 2025. Their propensity to mutate enables frequent immune evasion and high cross-species and human-human transmissibility which, combined with their seasonality, has made the development of vaccines that offer broad (i.e., covering many or all strains of a virus) and lasting protection difficult. The need for annual vaccine updates imposes a persistent economic burden whilst vaccine-strain match remains unreliable.
Influenza viruses exemplify these difficulties. Despite currently available vaccines preventing millions of cases each year (approximately 9.8 million in the US alone for the 2024/2025 season1), influenza causes around 1 billion cases (including 3 to 5 million severe cases) of illness and between 290,000 and 650,000 deaths globally each year2. Antigenic drift and occasional rapid antigenic shift3 allow influenza viruses to continuously evade immunity (both acquired and vaccine-induced), necessitating constant surveillance and annual vaccine reformulation to counter prevalent and newly emerging strains. Seasonal infection patterns, driven by climate, host behaviour, and co-circulation with other respiratory pathogens, further complicate prediction and preparedness4.
The World Health Organisation (WHO) Global Influenza Surveillance and Response System (GISRS)5 was established in 1952 and currently operates with networks across 130 WHO member states. The GISRS group hold biannual meetings, usually in February and September for the Northern and Southern hemispheres, respectively. At these meetings, experts review epidemiological data, genetic and antigenic characteristics, and vaccine effectiveness, before recommending which strains should be included in the upcoming season’s vaccines. The most recent recommendations for the Northern hemisphere were released in February 20256. Regulatory agencies, such as the US Food and Drug administration (FDA) and European Medicines Agency (EMA), may adjust which strains are included for their region, based on local epidemiological data.
Despite seasonal adjustments, emerging mutations still often lead to vaccine mismatch, causing influenza vaccine efficacy to vary significantly from year to year and by region. Since the 2004/2005 season, influenza vaccine efficacy estimates in the US have varied between 10% and 60%7.
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 in use since World War II and remain prevalent today due to the stronger and longer-lasting immunity they induce. More recently, their ability to be delivered intranasally (e.g., AstraZeneca’s “Fluenz” influenza vaccine) has been highly beneficial 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 induce a different and potentially weaker immune response compared with LAVs, often necessitating multiple doses or the addition of adjuvants. Inactivated virus vaccines, such as Sanofi’s quadrivalent influenza vaccine, remain in use today due to their favourable safety profile.
Both LAVs and inactivated virus vaccines work by introducing all or part of a virus to stimulate an immune response. Historically, they were produced in egg-based manufacturing processes which carried the risk of supply chain issues. Egg-adaptation changes to the viruses are also known to increase vaccine mismatch and lower effectiveness8. To bypass this, cell-based (i.e., grown in a cell culture) vaccines emerged, which also brought advantages of quicker and larger-scale production techniques, allowing more efficient responses to emerging strains and potential pandemics. In 2013, genetically engineered recombinant influenza vaccines entered the market. These vaccines are produced by producing synthetic viral DNA (in influenza’s case, the DNA that encodes the haemagluttinin [HA] protein) and inserting (recombining) it into the host virus’ genome. The host is then cultured to produce large quantities of the target protein, which is purified and formulated into the vaccine. Recombinant vaccines brought further manufacturing efficiencies and have been shown to induce greater immune responses than both egg- and cell-based vaccines9.
modRNA technology provides an exciting opportunity for the development of novel vaccines for influenza and other respiratory viruses. Unlike traditional vaccines, which directly introduce viral antigens to stimulate an immune response, synthetic modRNA is administered and then translated by the host cells to produce the viral antigen(s) encoded by the modRNA. The antigen(s) produced then may stimulate both humoral and cell-mediated immune responses.
The use of modRNA as a drug platform has been under study since the late 1980s. However, development was initially hampered by poor stability and unwanted innate immunogenicity through the activation of toll-like receptors10. In the early 2000s, breakthroughs in nucleoside modification (in particular, the creation of pseudouridine, an analogue of uridine) improved the stability of modRNA and reduced these undesirable immunogenic effects11.
The COVID-19 pandemic massively accelerated the approval of the first modRNA vaccines and highlighted their distinct advantages over traditional vaccine platforms: rapid development and scalable production. Once SARS-CoV-2 had been sequenced, scientists already working on modRNA rapidly designed SARS-CoV-2 vaccine candidates and clinical trials began a few months later. Within just 1 year of the virus being identified, 2 modRNA vaccines (developed by BioNTech/Pfizer and Moderna) had received emergency/conditional use authorisations from the FDA/EMA. The cell-free manufacturing process of modRNA vaccines could quickly be scaled up to meet the colossal demand imposed by the pandemic.
Initially, the modRNA vaccines, based on wild-type SARS-CoV-2 (Wuhan-Hu-1), were around 95% effective at reducing symptomatic COVID-1912. As new strains of SARS-CoV-2 emerged, protection against severe disease remained high but the vaccines’ overall efficacy began to wane. Formulations have been updated regularly to counter dominant strains, with both bivalent and monovalent vaccines being recommended in the years since by the WHO Technical Advisory Group on COVID-19 Vaccine Composition.
After the resounding success of modRNA vaccines in protecting against SARS-CoV-2, no time was wasted in the development of other modRNA vaccines. Last year, mRESVIA (a modRNA vaccine encoding the respiratory syncytial virus [RSV] fusion [F] protein) received FDA approval for adults aged 60 and older. modRNA vaccines for cytomegalovirus and Epstein-Barr virus are also in the early stages of development.
modRNA technology also provides an opportunity for the creation of universal vaccines (i.e., a vaccine which protects against all strains of a virus), by targeting conserved antigens (e.g., the stem of the HA, rather than the variable head). Universal modRNA vaccines for influenza and coronavirus, as well as a combined influenza and SARS-CoV-2 candidate, are currently being investigated in Phase 3 studies, with hopes for approval next year.
If universal modRNA vaccines prove to be successful in protecting against influenza and coronavirus variants, it will cement the 2020s as a new era for vaccine development. Not having to reformulate vaccines seasonally, combined with the inherent manufacturing benefits of modRNA vaccines, will massively reduce the economic burden of these diseases. Universal vaccines could potentially eradicate certain diseases in humans or at least eliminate their incidence in vaccinated regions. However, modRNA vaccines are not yet the perfect solution. Drawbacks include stronger reactogenicity and shorter duration of immunity than other vaccine types. Current ultra-cold storage requirements hinder distribution; producers will no doubt be focused on improving storage requirements to allow easier, cheaper, and more ubiquitous distribution.
At such a momentous time for vaccines, it is vital that their clinical development strategy is optimised and up to date with the latest innovations. Traditional vaccine field trials, where large cohorts of participants are vaccinated and then observed over a long period of time, can be a costly and inefficient gamble for candidate vaccines. These studies also suffer from low-quality data outputs (e.g., using proxy endpoints of influenzas-like illness instead of more specific and thorough viral load assessments) and struggle to assess efficacy against low circulation strains. The seasonality of respiratory viruses prevents field trials from adequately assessing efficacy before the vaccines are rolled out.
Human challenge trials (HCTs), also known as controlled human infection models (CHIMs), involve deliberately exposing 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 assess infection rates, viral load, and symptomology. The origins of HCTs can be traced 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 pioneered the concept of vaccines. Of course, HCTs have evolved significantly since then, adapting to modern ethical standards and regulations, and have contributed to the development of vaccines for diseases including influenza, dengue, norovirus, malaria, cholera, typhoid, and RSV. HCTs provide faster and more in-depth results. The controlled environment reduces variability, avoiding interference from other pathogens, and allowing more precise virological and immunological analysis. This permits the use of smaller sample sizes compared to traditional field studies and ultimately reduces the costs and risks of early-phase vaccine development.
hVIVO has an unparalleled history in HCTs. We conducted our first HCT in 2001 and in 2011 , we opened our first dedicated quarantine site and accompanying laboratories. When interest in HCTs was reignited by the urgency of the COVID-19 pandemic and in 2021, we expanded our quarantine facilities and conducted an HCT in 36 participants to characterise SARS-CoV-2. Overall, we have challenged over 5,000 participants with respiratory viruses and other pathogens, and have established human challenge models for contemporaneous influenza A and B, RSV A and B, hMPV, human rhinovirus, and SARS-CoV-2. Our integrated specialist virology laboratory has validated qualitative and quantitative assays for each of these viruses, allowing seamless operations throughout our studies.
Recent growth led to the opening of our flagship quarantine and laboratory site in Canary Wharf, London last year. The 50-bed quarantine facility is certified to work with pathogens up to biosafety level 3 (BSL3) and can work with multiple pathogens concurrently. hVIVO has the facilities and expertise to lead the way in this new era of vaccine development. Our HCTs can provide high-quality data efficiently, allowing your candidate vaccine or drug to succeed fast or fail fast. Our timely results could also help innovate the assessment and subsequent development of seasonal vaccines. We can develop models and assays for rare virus strains, which will be invaluable in the testing and approval of universal vaccines.
Canary Wharf’s on-site pharmacy, IMP facilities, and outpatient unit, and our dedicated project management and clinical teams are primed and ready to accelerate your vaccine or antiviral’s development. Our extensive participant database allows 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, was brought under the umbrella of 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. They work in close collaboration with hVIVO’s clinical site teams to ensure our clinical trials are executed to the highest scientific and regulatory standards.
In January 2025, we acquired CRS, an early-phase clinical research organisation based in Germany. We can now leverage their 2 clinical trial units and accompanying teams of experts to expand our overall site offering into the EU. The sites specialise in first-in-human studies as well as complex pharmacokinetic and pharmacodynamic studies in patients with renal or hepatic impairment. Our presence in Germany will allow our clients to capitalise on the recent proposals by the German Federal Ministry of Health for new Standard Contractual Clauses (SCs). Once finalised, these SCs will significantly shorten Clinical Trial Agreement (CTA) review times.
With our state-of-art quarantine unit and laboratories, as well as our expanded site and service offerings, the hVIVO group is undoubtedly the best placed CRO to drive the development of your vaccine or antiviral drug. Our experts can guide you throughout the whole product lifecycle, from feasibility through to the full execution of Phase 1 to 3 trials. Our human challenge models can improve the efficiency of the key early phases of your vaccine programme, whilst our increased capacity can be leveraged to run filed trials, which will still be essential to provide longer-term and robust safety data and for pathogens for which challenge trials would be unsuitable.
If you have questions or would like to find out more about our HCTs and other services, please contact us.
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